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This study aimed to investigate the ratio of excitatory and depressor post-stimulus manifestations of SI single neuron activity during VPL stimulation of the thalamic nucleus in a PD model to identify excitotoxicity in neurodegeneration and the formation of persistent pain, which is poorly treatable. Electrophysiological studies were performed on 6 albino rats (230±30 g): intact (n=3) and rotenone model (n=3) of Parkinson's disease (PD) induced by unilateral administration of rotenone for 4 weeks (n=3). We performed extracellular recordings of spike activity of 207 single neurons in the primary somatosensory cortex (SI) of the ventral posterolateral thalamic nucleus (VPL). Changes in depressor and excitatory responses (TD and TP), accompanied by post-tetanic depression and potentiation, were detected using the analysis. A significant excess in the frequency of the prestimulus (background) activity of SI neurons in a PD model was revealed as a result of the inevitable development of excitotoxicity. At the post-stimulus level, excitotoxicity under pathological conditions should also be recognized. In conclusion, the PD model revealed excitotoxicity in the SI neurons with the emergence of persistent chronic pain.

Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rotenone has widespread beneficial effects in agriculture, fisheries and animal husbandries; however prolonged exposure causes a detrimental effect on the health of personnel working in such industries. Rotenone during its extraction, formulation or usage may cross the blood brain barrier leading to neurodegeneration and the development of Parkinson's disease like symptoms. It is a known inhibitor of the mitochondrial ETC complex I and responsible for impairing the OXPHOS system. Our study showed that rotenone exposure results in an increased production of ROS and decreased ATP level along with a conspicuous loss of mitochondrial membrane potential in N2A cells. The transcription and expression pattern of cofilin, a key component of actin cytoskeleton, was also altered after rotenone exposure; leading to the actin cytoskeleton degradation. We further observed an increased expression, as well as activity of matrix metalloproteinase9 (MMP9) in rotenone exposed N2A cells; suggesting the involvement of inflammation upon rotenone exposure. Simultaneously, an opposite pattern was noticed for the tissue inhibitors of metalloproteinases-1 (TIMP-1) protein, which is a known modulator of MMP9 activity. Additionally, the localization of MMP9 along with alpha-synuclein, UCHL1 and cofilin suggested their close proximity and cross interaction upon rotenone treatment. Furthermore, we observed significant increase in the level of TNF-α upon rotenone exposure along with the phosphorylation of RIPK1, RIPK3 and MLKL that has been identified as the necroptosis markers leading to programmed necroptotic death., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work. We confirm that we have followed the regulations of our institutions concerning intellectual property. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the aging population. Particularly, long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in PD, while the role of lncRNA SNHG8 in PD remains to be further explored. C57BL/6 mice were induced by rotenone to establish a PD model in vivo, and then the dopaminergic (DA) neuronal damage and locomotor dysfunction in rotenone-treated mice were evaluated. Murine DA cell line MN9D was treated with rotenone to establish a cellular PD model in vitro. Then, the viability, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells were assessed. Expression levels of SNHG8, microRNA-421-3p (miR-421-3p), and sorting nexin 8 (SNX8) in the substantia nigra (SN) of PD mice and rotenone-treated MN9D cells were detected. The interaction between SNHG8 and miR-421-3p, and the targeting relationship between SNX8 and miR-421-3p were confirmed. SNHG8 and SNX8 expression levels were decreased while miR-421-3p expression level was increased in the SN of PD mice and rotenone-treated MN9D cells. Upregulated SNHG8 ameliorated dopaminergic neuron damage and locomotor dysfunction in PD mice. Meanwhile, upregulated SNHG8 enhanced viability, diminished apoptosis, and alleviated mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells. Mechanistically, SNHG8 bound to miR-421-3p, and miR-421-3p targeted SNX8. Overexpressed SNHG8 downregulates miR-421-3p to alleviate rotenone-induced dopaminergic neuron injury in PD via upregulating SNX8., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Considering the central role of oxidative stress in the onset and progress of Parkinson's diseases (PD), search for compounds with antioxidant properties has attracted a growing body of attention. Here, we compare the neuroprotective effect of bulk and nano forms of the polyphenolic fraction of propolis (PFP) against rotenone-induced cellular and animal models of PD. Mass spectrometric analysis of PFP confirmed the presence of multiple polyphenols including kaempferol, naringenin, coumaric acid, vanillic acid, and ferulic acid. In vitro cellular experiments indicate the improved efficiency of the nano form, compared to the bulk form, of PFP in attenuating rotenone-induced cytotoxicity characterized by a decrease in cell viability, release of lactate dehydrogenase, increased ROS generation, depolarization of the mitochondrial membrane, decreased antioxidant enzyme activity, and apoptosis induction. In vivo experiments revealed that while no significant neuroprotection was observed relating to the bulk form, PFP nanosheets were very effective in protecting animals, as evidenced by the improved behavioral and neurochemical parameters, including decreased lipid peroxidation, increased GSH content, and antioxidant enzyme activity enhancement. We suggest that improved neuroprotective effects of PFP nanosheets may be attributed to their increased water solubility and enrichment with oxygen-containing functional groups (such as OH and COOH), leading to increased antioxidant activity of these compounds.

Yucca aloifolia L. fruit (Yucca or Spanish bayonet, family Asparagaceae) is recognized for its purplish red color reflecting its anthocyanin content, which has a powerful antioxidant activity. This study aimed to investigate yucca (YA) fruit extract's protective effect on Parkinson's disease (PD). In vitro study, the anti-inflammatory activity of yucca fruit extracts was explored by measuring tumor necrosis factor receptor 2 (TNF-R2) and nuclear factor kappa B (NF-KB) to choose the most effective extract. Afterward, a detailed in vivo investigation of the protective effect of the most active extract on rotenone-induced PD was performed on male albino Wister rats. First, the safety of the extract in two different doses (50 and 100 mg/kg in 0.9% saline orally) was confirmed by a toxicological study. The rats were divided into four groups: 1) normal control (NC); 2) rotenone group; and third and fourth groups received 50 and 100 mg/kg yucca extract, respectively. The neurobehavioral and locomotor activities of the rats were tested by rotarod, open field, and forced swim tests. Striatal dopamine, renal and liver functions, and oxidative stress markers were assessed. Western blot analysis of brain tissue samples was performed for p-AMPK, Wnt3a, and β-catenin. Histopathological examination of striatal tissue samples was performed by light and electron microscopy (EM). The metabolites of the active extract were characterized using high-resolution LC-MS/MS, and the results showed the prevalence of anthocyanins, saponins, phenolics, and choline. Biochemical and histopathological tests revealed a dose-dependent improvement with oral Yucca extract. The current study suggests a possible neuroprotective effect of the acidified 50% ethanol extract (YA-C) of the edible Yucca fruit, making it a promising therapeutic target for PD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recently, phosphodiesterases (PDEs) have gained great attention due to their implication in Parkinson's disease (PD) pathogenesis. Noteworthy, the PDE4 enzyme is highly expressed in the striatum and selectively degrades cyclic adenosine monophosphate (cAMP). The cAMP was shown to play a vital role in dopamine (DA) signaling besides maintaining the plasticity of dopaminergic neurons as well as protecting them from inflammation and oxidative stress-mediated death. Thus, PDE4 inhibition could be a promising strategy for treating PD. Accordingly, the present study investigated the neuroprotective efficacy of roflumilast, a PDE4 inhibitor, in abolishing neurodegeneration in the rotenone-induced PD model. Rotenone (1.5 mg/kg, s.c) was delivered via 11 injections on matching days. Roflumilast treatment (0.5 mg/kg, p.o) was given daily after the fifth rotenone injection. Roflumilast significantly reversed rotenone's adverse effects, as it enhanced trophic factors expression and abrogated inflammation as well as oxidative stress. Thus, promoting dopaminergic neuronal plasticity and survival, as well as restoring striatal DA level and function, which resulted in enhanced motor performance. The beneficial effect of roflumilast was mediated through inhibition of striatal PDE4 with consequent activation of cAMP-dependent protein kinase A (PKA) signaling pathways, including the cAMP response element-binding protein (CREB) pathway and dopamine and cAMP-regulated phosphoprotein 32,000 (DARPP-32) pathway that is essential for maintaining dopaminergic function. Therefore, the present work sheds light on the substantial neuroprotective potential of roflumilast in treating PD through the activation of the cAMP/PKA cascade., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

While all current therapies' main focus is enhancing dopaminergic effects and remission of symptoms, delaying Parkinson's disease (PD) progression remains a challenging mission. Linagliptin, a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, exhibited neuroprotection in various neurodegenerative diseases. This study aims to evaluate the neuroprotective effects of Linagliptin in a rotenone-induced rat model of PD and investigate the possible underlying mechanisms of Linagliptin's actions. The effects of two doses of Linagliptin (5 and 10 mg/kg) on spontaneous locomotion, catalepsy, coordination and balance, and histology were assessed. Then, after Linagliptin showed promising results, it was further tested for its potential anti-inflammatory, antiapoptotic effects, and different pathways for oxidative stress. Linagliptin prevented rotenone-induced motor deficits and histological damage. Besides, it significantly inhibited the rotenone-induced increase in pro-inflammatory cytokines: Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) and decrease in caspase 3 levels. These effects were associated with induction in the levels of Protein deglycase also known as DJ-1, Hypoxia-inducible factor 1-alpha (HIF-1α), potentiation in the Sirtuin 1 (SIRT-1)/Nuclear factor erythroid-2-related factor 2 (Nrf-2)/Heme oxygenase-1 (HO-1) pathway, and an increase in the antioxidant activity of catalase which provided neuroprotection to the neurons from rotenone-induced PD. Collectively, these results suggest that Linagliptin might be a suitable candidate for the management of PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The neuropathology of Parkinson's disease (PD) is complex and affects multiple systems of the body beyond the central nervous system. This study examined the effects of gallic acid (GA) and gastrointestinal vagotomy (VG) on motor, cognitive, intestinal transit time, and thalamic nuclei electrical power in an animal model of PD induced by rotenone., Materials and Methods: Male Wistar rats were divided into 4 groups: Sham, ROT, ROT+GA, VG + ROT. Sham rats received vehicle, those in ROT received rotenone (5 mg/kg/2 ml, ig), PD rats in ROT+GA were treated with GA (100 mg/kg, gavage/once daily, for 28 days), and in VG + ROT, the vagal nerve was dissected. Stride length, motor coordination and locomotion, intestinal transit time, cognitive and pain threshold, and thalamic local EEG were evaluated. Oxidative stress indexes in striatal tissue were also measured., Results: Rotenone diminished significantly the stride length (p < 0.001), motor coordination (p < 0.001), power of thalamic EEG (p < 0.01) and pain (p < 0.001). MDA increased significantly (p < 0.001) while GPx activity decreased (p < 0.001). Intestinal transit time rose significantly (p < 0.01). PD rats treated with GA improved all above disorders (p < 0.001, p < 0.01). Vagotomy prevented significant alterations of motor and non-motor parameters by rotenone., Conclusion: According to current findings, rotenone acts as a toxin in GI and plays a role in the pathogenesis of PD through gastric vagal nerve. Thus, vagotomy could prevent the severity of toxicity by rotenone. In addition, GA improved symptoms of PD induced by rotenone. Therefore, GA can be regarded as a promising therapeutic candidate for PD patients., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Major pathological features of Parkinson's disease (PD) include increase in oxidative stress leading to the aggregation of α-synuclein, mitochondrial dysfunction and apoptosis of dopaminergic neurons. In addition, downregulation of the expression of neurotrophic factors like-Brain Derived Neurotrophic Factor (BDNF) is also involved in PD progression. There has been a lot of interest in trophic factor-based neuroprotective medicines over the past few decades to treat PD symptoms. Rotenone, an insecticide, inhibits the mitochondrial complex I causing overproduction of ROS, oxidative stress, and aggregation of α-synuclein. It has been shown that BDNF and Tropomyosin receptor kinase B (TrkB) interaction initiates the regulation of neuronal cell development and differentiation by the serine/threonine protein kinases like Akt and GSK-3β. Additionally, Transcription factor CREB (cAMP Response Element-binding protein) also determines the gene expression of BDNF. The homeostasis of these signalling cascades is compromised with the progression of PD. Therefore, maintaining the equilibrium of these signalling cascades will delay the onset of PD. Oleuropein (OLE), a polyphenolic compound present in olive leaves has been documented to cross blood brain barrier and shows potent antioxidative property. In the present study, the dose of 8, 16 and 32 mg/kg body weight (bwt) OLE was taken for dose standardisation. The optimised doses of 16 and 32 mg/kg bwt was found to be neuroprotective in Rotenone induced PD mouse model. OLE improves motor impairment and upregulate CREB regulation along with phosphorylation of Akt and GSK-3β in PD mouse. In addition, OLE also reduces the mitochondrial dysfunction by activation of enzyme complexes and downregulates the proapoptotic markers in Rotenone intoxicated mouse model. Overall, our study suggests that OLE may be used as a therapeutic agent for treatment of PD by regulating BDNF/CREB/Akt signalling pathway., (© 2023. The Author(s).)

Background: Several results demonstrated that microglia and peripheral monocytes/macrophages infiltrating the central nervous system (CNS) are involved in cell response against toxic compounds. It has been shown that rotenone induces neurodegeneration in various in vitro experimental models. Baicalin, a natural compound, is able to attenuate cell damage through anti-oxidant, anti-microbial, anti-inflammatory, and immunomodulatory action. Using THP-1 monocytes, we investigated rotenone effects on mitochondrial dysfunction and apoptosis, as well as baicalin ability to counteract rotenone toxicity., Methods and Results: THP-1 cells were exposed to rotenone (250 nM), in the presence/absence of baicalin (10-500 μM) for 2-24 h. Reactive Oxygen Species production (ROS), mitochondrial activity and transmembrane potential (Δψm), DNA damage, and caspase-3 activity were assessed. Moreover, gene expression of mitochondrial transcription factor a (mtTFA), interleukin-1β (IL-1β), B-cell lymphoma 2 (Bcl2) and BCL2-associated X protein (Bax), together with apoptotic morphological changes, were evaluated. After 2 h of rotenone incubation, increased ROS production and altered Δψm were observed, hours later resulting in DNA oxidative damage and apoptosis. Baicalin treatment at 50 µM counteracted rotenone toxicity by modulating the expression levels of some proteins involved in mitochondrial biogenesis and apoptosis. Interestingly, at higher baicalin concentrations, rotenone-induced alterations persisted., Conclusions: These results give evidence that exposure to rotenone may promote the activation of THP-1 monocytes contributing to enhanced neurodegeneration. In this context, baicalin at low concentration exerts beneficial effects on mitochondrial function, and thus may prevent the onset of neurotoxic processes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The botanical pesticide rotenone can effectively control target pest Plutella xylostella , yet insights into in situ metabolic regulation of P. xylostella toward rotenone remain limited. Herein, we demonstrated metabolic expression levels and spatial distribution of rotenone-treated P. xylostella using spatial metabolomics and lipidomics. Specifically, rotenone significantly affected purine and amino acid metabolisms, indicating that adenosine monophosphate and inosine were distributed in the whole body of P. xylostella with elevated levels, while guanosine 5'-monophosphate and tryptophan were significantly downregulated. Spatial lipidomics results indicated that rotenone may significantly destroy glycerophospholipids in cell membranes of P. xylostella , inhibit fatty acid biosynthesis, and consume diacylglycerol to enhance fat oxidation. These findings revealed that high toxicity of rotenone toward P. xylostella may be ascribed to negative effects on energy production and amino acid synthesis and damage to cell membranes, providing guidelines for the toxicity mechanism of rotenone on target pests and rational development of botanical pesticide candidates.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic cells in the substantia nigra pars compacta. PD patients' brains show neuroinflammation, oxidative stress, and mitochondrial dysfunction. The present study aims to evaluate the neuroprotective activity of VD3 on astrocytes after their exposure to rotenone (ROT) a natural pesticide known to exhibit neurotoxic potential via the inhibition of mitochondrial complex I. Cell viability parameters were evaluated by the MTT test and staining with 7-AAD in cultures of astrocytes treated and untreated with VD3 (0.1, 0.5, and 1.0 ng/mL) and/or ROT (10 µg/mL or 5 µg/mL), and the cytoplasmic production of ROS and the cell death profile were measured by flow cytometry. Glutathione accumulation and ultrastructural changes were evaluated and immunocytochemistry assays for NF-kB and Nrf2 were also carried out. The results showed that VD3 improved the viability of cells previously treated with VD3 and then exposed to ROT, reducing the occurrence of necrotic and apoptotic events. Furthermore, cells exposed to ROT showed increased production of ROS, which decreased significantly with previous treatment with VD3. Importantly, the decrease by ROT in the mitochondrial transmembrane potential was significantly prevented after treating cells with VD3, especially at a concentration of 1 ng/mL. Therefore, treatment with VD3 protected astrocytes from damage caused by ROT, decreasing oxidative stress, decreasing NF-kB and Nrf2 expressions, and improving mitochondrial function. However, further investigation is needed regarding the participation and mechanism of action of VD3 in this cellular model of PD focusing on the crosstalk between Nrf2 and NF-kB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1β levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.

Parkinson's disease (PD) is characterized by dopaminergic cell loss in the substantia nigra, and PD brains show neuroinflammation, oxidative stress, and mitochondrial dysfunction. The study evaluated the neuroprotective activity of 1α,25-dihydroxy vitamin D3 (VD3), on the rotenone (ROT)-induced cytotoxicity in PC12 cells. The viability parameters were assessed by the MTT and flow cytometry, on cells treated or not with VD3 and/or ROT. Besides, ROS production, cell death, mitochondrial transmembrane potential, reduced GSH, superoxide accumulation, molecular docking (TH and Keap1-Nrf2), and TH, Nrf2, NF-kB, and VD3 receptor protein contents by western blot were evaluated. VD3 was shown to improve the viability of ROT-exposed cells. Cells exposed to ROT showed increased production of ROS and superoxide, which decreased after VD3. ROT decrease in the mitochondrial transmembrane potential was prevented, after VD3 treatment and, VD3 was shown to interact with tyrosine hydroxylase (TH) and Nrf2. While ROT decreased TH, Nrf2, and NF-kB expressions, these effects were reversed by VD3. In addition, VD3 also increased VD3 receptor protein contents and values went back to those of controls after ROT exposure. VD3 protects PC12 cells against ROT damage, by decreasing oxidative stress and improving mitochondrial function. One target seems to be the TH molecule and possibly an indirect Nrf2 activation could also justify its neuroprotective actions on this PC12 cell model of PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Exposure to environmental toxicants has been linked with the onset of different neurodegenerative diseases in animals and humans. Here, we evaluated the toxic effects of co-exposure to iron and rotenone at low concentrations in Drosophila melanogaster. Adult wild-type flies were orally exposed to rotenone (50.0 µM) and ferrous sulfate (FeSO 4 ; 1.0 and 10.0 µM) through the diet for 10 days. Thereafter, we evaluated markers of oxidative damage (Hydrogen Peroxide (H 2 O 2 ), Nitric Oxide (NO), Protein Carbonyl, and malondialdehyde (MDA)), antioxidant status (catalase, Glutathione S-Transferase (GST), Total Thiol (T-SH) and Non-protein Thiol (NPSH), neurotransmission (monoamine oxidase; MAO and acetylcholinesterase, AChE) and mitochondrial respiration. The results indicated that flies fed rotenone and FeSO 4 had impaired locomotion, reduced survival rate, and AChE activity with a corresponding increase in MAO activity when compared with the control (p < 0.05). Furthermore, rotenone and FeSO 4 significantly decreased the antioxidant status with a concurrent accumulation of NO, MDA, and H 2 O 2 . Additionally, the activity of complex 1 and mitochondria bioenergetic capacity was compromised in the flies. These findings suggest that the combination of rotenone and FeSO 4 elicited a possible synergistic toxic response in the flies and therefore provided further insights on the use of D. melanogaster in toxicological studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The paper examines the use of natural antioxidant and anti-inflammation substances as therapeutic candidates for brain disease. Para-coumaric acid (pCA), a phenolic compound with a variety of medicinal properties, was used against deterioration caused by various diseases. Recently, pCA has gained attention for use against cardiovascular disease but less so for neurodegenerative disease (i.e., Parkinson's disease). Therefore, the present study intended to investigate the effect of pCA against rotenone-induced Parkinson's disease-like pathology in mice. Thirty male institute of cancer research (ICR) mice were randomly divided into three experimental groups: Sham-veh, Rot-veh, and Rot-pCA100. Rotenone (Rot) 2.5 mg/kg was subcutaneously injected every 48 h in the rotenone groups. Alternately, a 100 mg/kg pCA dose was given every 48 h via intragastric gavage to the Rot-pCA100 group for 6 weeks. Motor ability was assessed at the second, fourth, and sixth week before brain collection for biochemical and histological analyses. Results indicated significant motor deficits appeared from the second to sixth week after rotenone injection. Brain analysis detected a significant effect of rotenone in the increase of malondialdehyde and tumor necrosis factor-alpha (TNF-α). This result was observed in accordance with a reduction of tyrosine hydroxylase (TH) and an increase of neuronal degeneration in the substantia nigra par compacta (SNc) and striatum. However, pCA was able to reverse all of the deterioration (i.e., reduced malondialdehyde and TNF-α) rotenone had caused, and it protected against TH and neuronal loss in the SNc and striatum. Therefore, the present study has depicted the neuroprotective effect of pCA against rotenone-induced Parkinson's disease-like pathology in mice. Benefits of pCA include anti-lipid peroxidation and anti-inflammatory effects, inhibition of neurodegeneration, and a nurturing effect on the TH level in the SNc and striatum, leading to mitigation of motor deficits., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objective: This investigation explores the neuroprotective effect of PIASA, a newly designed peptide, VCSVY, in in-silico and in opposition to rotenone stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in an SH-SY5Y cellular model., Methods: Docking and visualization of the PIASA and rotenone were progressed against mitochondrial respiratory complex I (MCI). The in-silico analysis showed PIASA to have interaction with the binding sites of rotenone, which may reduce the rotenone interaction and its toxicity too. The SH-SY5Y cells were segregated into four experimental groups: Group I: untreated control cells; Group II: rotenone-only (100 nM) treated cells; Group III: PIASA (5 μM) + rotenone (100 nM) treated cells; and Group IV: PIASA-only (5 μM) treated cells., Results: We evaluated the cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), apoptosis (dual staining technique), nuclear morphological changes (Hoechst staining technique), the expressions of BAX, Bcl-2, cyt c, pro-caspase 3, and caspase 3, -6, -8, -9, and cleaved caspase 3 by western blot analysis. In SH-SY5Y cells, we further observed the cytotoxicity, oxidative stress and mitochondrial dysfunction in rotenone-only treated cells, whereas pretreatment of PIASA attenuated the rotenone-mediated toxicity. Moreover, rotenone toxicity is caused by complex I inhibition, which leads to mitochondrial dysfunction, increased BAX expression, while downregulating the Bcl-2 expression and cyt c release, and then finally, caspases activation. PIASA pretreatment prevented the cytotoxic effects via the normalization of apoptotic marker expressions influenced by rotenone. In addition, pre-clinical studies are acceptable in rodents to make use of PIASA as a revitalizing remedial agent, especially for PD in the future., Conclusion: Collectively, our results propose that PIASA mitigated rotenone-stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in rotenone-induced SH-SY5Y cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Parkinson's disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities., Objective: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axisMethods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) and autophagic (mTOR, Atg5,7, p62, Beclin,LC3B-I/II) protein activity were evaluated both in in vitro and in vivo., Results: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein., Conclusion: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.

Rotenone is a botanical pesticide and has long been used for control of insect pests and also as a natural piscicide for management of fish populations in many countries. Field application for pest control, however, often encounters the movement of rotenone into surface water due to spray drift or surface runoff after rainfall, which could potentially result in water pollution and unexpected death of fishes. To minimize its effect on freshwater and the problem of fish dying, one solution was to encapsulate rotenone in specific microspheres, limiting its release and reducing its toxicity since rotenone can be quickly degraded under sunlight. In this study, pH-responsive alginate-based microspheres were synthesized to encapsulating rotenone, which were designated as rotenone beads. The rotenone beads, along with alginate beads (devoid of rotenone) were characterized and evaluated for their responses to pH and effects on zebrafish. Results showed that the microspheres had high loading efficiency (4.41%, w/w) for rotenone, and rotenone beads well responded to solution pH levels. The cumulative release rates of rotenone from the beads were 27.91%, 42.72%, and 90.24% at pH 5.5, 7.0, and 9.0, respectively. Under acidic conditions, the rotenone release rate was lower due to hydrogen bonding. On the contrary, rotenone became more quickly released at the high pH due to intermolecular repulsion. The toxicity of rotenone beads to zebrafish and fish embryos at a pH of 5.5 was reduced by 2- and 4-fold than chemical rotenone. Since pH levels in most freshwater lakes, ponds, and streams vary from 6 to 8, rotenone release from the beads in such freshwater could be limited. Thus, the synthesized rotenone beads could be relatively safely used for pest control with limited effects on freshwater fishers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Parkinsonism is characterized by degeneration of dopaminergic neurons and impairment in neuroplasticity. Empagliflozin (EMPA) is an anti-diabetic drug that has been shown to improve cognitive dysfunctions and exerted antioxidant and anti-inflammatory effects in different models. This study aimed to determine the neuroprotective effects of EMPA against rotenone (ROT)-induced parkinsonism., Main Methods: ROT (1.5 mg/kg) was injected subcutaneously three times per week for two successive weeks. Mice were treated with EMPA (3 and 10 mg/kg, orally) for one week prior ROT administration and for another two weeks along with ROT. After that, motor functions and histopathological changes were assessed, and brains were isolated for biochemical analyses and immunohistochemical investigation., Key Findings: Results indicated that, in a dose dependent manner, EMPA improved motor functions and histopathological changes induced by ROT, increased brain content of reduced glutathione (GSH), dopamine (DA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear factor erythroid 2-related factor 2 (Nrf2), inositol trisphosphate (IP3), calcium (Ca 2+ ), calcium/calmodulin-dependent protein kinase type IV (CaMKIV) and phospho-Protein kinase B (p-Akt) levels compared to ROT group. Additionally, EMPA decreased the levels of malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), and inactivated glycogen synthase kinase-3 beta (GSK-3β). Improvement in neuroplasticity was also observed indicated by elevation in brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and neuronal PAS domain Protein 4 (Npas4)., Significance: EMPA improved motor functions possibly through improving neuroplasticity markers and antioxidant, anti-inflammatory, and neuroprotective effects in a dose dependent manner., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Glaucoma is one of the most common causes of blindness worldwide. It is thought to be a multifactorial disease with underlying mechanisms that include mitochondrial dysfunction and oxidative stress. Here, we used NF-E2 related factor 2 (Nrf2) knockout (KO) mice, which are vulnerable to oxidative stress, to examine a neuroprotective effect against oxidative stress due to rotenone, a mitochondrial complex I inhibitor. Wild-type (WT) and Nrf2 KO mice received an oral solution of rotenone for 30 days. We then extracted the retinas and performed immunohistochemistry and quantitative RT-PCR. We also prepared a primary Müller cell culture of samples from each mouse, added 30 μM rotenone, and then measured cell viability, cytotoxicity and CellRox absorbance. We also examined gene expression. We found a significant increase in the number of 8-OHdG-positive retinal ganglion cells (RGCs) after rotenone administration in both the WT and Nrf2 KO mice. There was no difference in the number of RNA-binding protein with multiple splicing (RBPMS)-positive RGCs in the WT and Nrf2 KO mice, but Nrf2 KO mice that were given rotenone had significantly less retinal gene expression of RBPMS than Nrf2 KO mice given a control. Moreover, there was significantly higher mRNA gene expression of vimentin and glial fibrillary acidic protein (GFAP) in Nrf2 KO mice that received rotenone than WT mice that received rotenone. A statistical analysis of the in vitro experiment showed that cell viability was lower, cytotoxicity was higher, and oxidative stress was higher in the Müller cells of the Nrf2 KO mice than the WT mice. Finally, brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) were significantly higher in the Müller cells of the Nrf2 KO mice than the WT mice. These findings suggest that in Nrf2 KO mice under oxidative stress caused by rotenone, temporary neurotrophic factors are secreted from the Müller cells, conferring neuroprotection in these cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative illness described as damage to dopaminergic neurons. There is increasing evidence that neuroinflammatory activity mediated by microglia is extensively involved in the initiation and development of PD. This study assessed the protective effect of evening primrose oil [EPO] as an anti-inflammatory mediator in rotenone-induced Parkinsonism in rats. Forty-eight adult male albino rats were distributed into four groups. Group I: control. Group II: rotenone [1.5 mg/kg/48 h] was administered subcutaneously to the rats. Groups III and IV: the rats had rotenone plus daily oral [EPO] 5 and 10 mg/kg respectively. After 24 days, motor behaviour was assessed by the open field and rotarod tests. The brain striata were isolated and tested for tumor necrosis factor (TNF)-α, interleukin 6, NF-B [nuclear factor-kappa B], and dopamine levels. The mid-brain tissues were processed for light and electron microscopy examinations, and immunohistochemical staining for tyrosine hydroxylase [TH], and microglia cells' markers: [CD68 and IBA1]. Results revealed that rotenone-treated rats had poor motor function, a significantly increased striatal level of inflammatory markers, markedly shrunken neurons, degeneration, pyknotic neuroglia, neuropil vacuolation, markedly destructed swollen mitochondria with loss of their cristae, and dilated rough endoplasmic reticulum, as well as decreased TH and increased CD68 and IBA1-positive cells. Treatment with EPO ameliorates all the neuropathological changes of rotenone in the rat brain. In conclusion, EPO enhanced the motor performance, reduced the inflammatory marker levels, restored dopamine levels, and ameliorated the neurohistopathological lesions of rats with experimental parkinsonism, suggesting its neuroprotective and anti-inflammatory effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown. Therefore, this study aims to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated. First, rotenone induced cell toxicity and α-Syn aggregation, with a significant reduction of SUMOylation and autophagy. Boosting SUMOylation prevented α-Syn aggregation, phosphorylation and recovery of autophagy. Moreover, α-Syn 140 and α-Syn 126 were SUMOylated while the other two isoforms, α-Syn 112 and 98 were not and their overexpression showed that were more toxic and induced more α-Syn aggregation. Rotenone increased their toxicity that was not affected by boosting SUMOylation. These results may indicate a role of SUMOylation in modulating α-Syn aggregation, inducing to understanding more about the behavior of α-Syn isoforms., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a movement disorder resulting from the loss of dopaminergic neurons over time. While there is no cure for PD, available conventional therapies aid to manage the motor symptoms. Natural products (NPs) derived from plants are among the most potent alternative therapies for PD. This study explored the neuroprotective potential of selected cinnamoyl derivatives namely toussaintine A (1), E-toussaintine E (2), asperphenamate (3) and julocrotine (4) against PD indicators using rotenone-challenged Drosophila melanogaster and in silico models. The compounds were first assessed for their toxicity preceding treatment experiments. Adult flies (aged 1-4 days) were exposed to varying concentrations of the compounds for 7 days. During the experiment, the mortality of flies was observed, and the lethal concentration (LC 50 ) of each tested compound was determined. The LC 50 values were found to be 50.1, 55.6, 513.5, and 101.0 µM for compounds 1, 2, 3, and 4, respectively. For seven days, we exposed flies to 500 µM of rotenone and co-fed with a chosen dose of 40 µM of each test compound in the diet. Using a negative geotaxis test, rotenone-challenged flies exhibited compromised climbing ability in comparison to control flies, the condition that was reversed by the action of studied compounds. Rotenone exposure also elevated malondialdehyde levels in the brain tissues, as measured by lipid peroxidation, when compared to control flies. In flies exposed to rotenone and co-fed with the compounds, this effect was lessened. In flies exposed to rotenone, mRNA levels of antioxidant enzymes such as superoxide dismutase and catalase were raised but were normalized in flies treated with the investigated compounds. Moreover, in-silico studies examined the inhibitory ability of compounds 1-4 against selected PD molecular targets, revealing the strong power of toussaintine A (1) against Adenosine receptor 2 (A2AR) and monoamine oxidase B. Thus, our findings suggest that cinnamoyl derivatives have neuroprotective potential via reducing the oxidative burden and improving locomotor ability after toxin invectives. In particular, compound 1 at lower doses can simultaneously be a potential inhibitor of A2AR and an anti-oxidative mediator in the development of anti-PD agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

3,4-dihydroxyphenethylamine (dopamine) depletion, inhibition of complex I activity, oxidative stress, and glutamate excitotoxicity are cardinal biochemical features of neurotoxicity induced by systemic unilateral infusion of rotenone. Kolaviron (KV), a biflavonoid from Garcinia kola seeds, has been proven to have pharmacological effects against neurotoxicity. Coenzyme Q10 plays an essential role in mitochondrial oxidative phosphorylation and as an antioxidant. This study examined the comparative influence of kolaviron and coenzyme Q10 on complex I activity, dopamine metabolism, glutamate clearance, and redox stress in rotenone-induced neurotoxicity in the cortex, hippocampus, and striatum of the brain of rats. Adult Male Wistar rats were pretreated with 200 mg/kg KV or 100 mg/kg coenzyme Q10 for 7 days followed by administration of a progressive six doses of 1.5 mg/kg rotenone within the next 48 h after which the animals were euthanized and the brain excised. On the cortical, hippocampal, and striatal regions of the brain, complex I activity, dopamine metabolism, oxidative stress markers, as well as glutamate metabolism were carried out and analyzed. In all brain regions examined, KV and coenzyme Q10 pretreatment modulated complex I activity, ameliorated redox imbalance, and enhanced dopamine metabolism via increasing the activity of tyrosine hydroxylase and decreasing monoamine oxidase activity. KV facilitated glutamate clearance through augmentation of glutamate dehydrogenase and glutamine synthetase activities.  The activity of KV was comparable to that of the mitochondrial membrane antioxidant compound, coenzyme Q10, this indicates that KV is a promising therapeutic agent in the treatment of Parkinson's disease and its activity compares well with coenzyme Q10.

In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT 6 R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT 6 R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT 6 R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g , which behaves as a neutral antagonist at the 5-HT 6 R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT 6 R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.

Parkinson's disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive impairment. To test this in PD, we promoted a lesion within the substantia nigra pars compacta of rats using the neurotoxin rotenone. In the sequence, the animals were supplemented with folic acid and vitamin B12 for 14 consecutive days and subjected to the object recognition test. We observed an impairment in object recognition memory after rotenone administration, which was prevented by supplementation ( p < 0.01). Supplementation may adjust gene expression through efficient DNA methylation. To verify this, we measured the expression and methylation of the kynureninase gene ( Kynu ), whose product metabolizes neurotoxic metabolites often accumulated in PD as kynurenine. Supplementation prevented the decrease in Kynu expression induced by rotenone in the substantia nigra ( p < 0.05), corroborating the behavioral data. No differences were observed concerning the methylation analysis of two CpG sites in the Kynu promoter. Instead, we suggest that folic acid and vitamin B12 increased global DNA methylation, reduced the expression of Kynu inhibitors, maintained Kynu-dependent pathway homeostasis, and prevented the memory impairment induced by rotenone. Our study raises the possibility of adjuvant therapy for PD with folic acid and vitamin B12.

Dyskinesia is characterized by abnormal involuntary movements (AIMs). Such movements are considered restrictive problem associated with the chronic use of L-dopa in Parkinson's disease (PD) treatment; the thing that renders the definite pathological mechanism unclear. However, there is a correlation between excitotoxicity of glutamatergic NMDA receptors, neuroinflammation, and oxidative stress in the lesioned nigrostriatal pathway; which mediates the firing of basal ganglia neurons involved in dyskinesia., Aims: The current study investigated the novel neuroprotective effect of agmatine in ameliorating both PD and dyskinesia with a focus on its antioxidant, anti-inflammatory, and anti-apoptotic potentiality through Nrf2 activation and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling pathway., Main Methods: PD was induced in animals by ten consecutive doses of rotenone (3 mg/kg/day; s.c.). Agmatine (100 mg/kg/day; i.p.) was injected for 16 days after modeling PD either alone or in combination with L-dopa/carbidopa (50/25 mg/kg/day; i.p.)., Key Findings: A statically significant deteriorating effect was showed on the behavioral, neurochemical, histopathological, and immunochemical analysis of PD rats. Moreover, dyskinesia observed in PD rats that received L-dopa. Agmatine improved animals' behavior and abolished dyskinetic AIMs. It inhibited NMDA receptors expression in nigral tissues leading to inhibition of inflammatory and oxidative stress cascades. It increased both nigral TH immunoreactive cells and striatal dopamine contents. Besides, it increased the antioxidant defense mechanism of Nrf2/TAC contents along with a significant decrease of HMGB1/RAGE/TLR4/MYD88/NF-κB protein expression., Significance: The current investigated data signifies the novel role of agmatine in ameliorating both PD and dyskinesia through mediating NMDA receptors, Nrf2, and HMGB1/RAGE/TLR4/NF-κB signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mitochondria generate energy through the action of the electron transport chain (ETC) and ATP synthase. Mitochondrial malfunction can lead to various disorders, including neurodegenerative diseases. Several reports have shown that menaquinone-4 (MK-4, vitamin K 2(20) ), a safe drug for osteoporosis, may improve mitochondrial function. Here, we hypothesized that the efficient delivery of menahydroquinone-4 (MKH), an active form of MK-4, could exert a supporting effect. We verified the effects of MKH delivery on mitochondrial dysfunction by using MK-4 and MKH ester derivatives in NIH/3T3 mouse fibroblast cells treated with mitochondrial inhibitors. MK-4 and MKH derivatives suppressed cell death, the decline in mitochondrial membrane potential (MMP), excessive reactive oxygen species (ROS) production, and a decrease in intrinsic coenzyme Q 9 (CoQ 9 ) induced by rotenone (ROT, complex I inhibitor). MK-4 and MKH derivatives delivered MKH to NIH/3T3 cells, acting as an effective MKH prodrug, proving that the delivered MKH may reflect the mitigation effects on ROT-induced mitochondrial dysfunction. MKH prodrugs are also effective against 3-nitropropionic acid (3-NP, complex II inhibitor) and carbonyl cyanide-m-chlorophenylhydrazone (CCCP, uncoupler)-induced cell death. In conclusion, MKH delivery may mitigate mitochondrial dysfunction by maintaining MMP, ROS, and CoQ 9 , indicating that MKH prodrugs may be good candidates for treating mitochondrial disorders., (© 2022. The Author(s).)

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3β through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rotenone is a commercial pesticide commonly used to model Parkinson's disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that rotenone causes microglial activation, which seems to contribute to the toxic effects seen in rodent models. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related neuropeptides that have robust neuroprotective and anti-inflammatory properties. However, their ability to regulate microglial activity in response to rotenone is not fully understood. Using rotenone as an inflammatory stimulus, we tested whether PACAP or VIP could mitigate microglial activation in BV2 microglial cells. Rotenone dose-dependently reduced cell viability and the percentage of apoptotic cells. It also increased the release of nitric oxide (NO) in culture media and the expression of microglial activation markers and pro-inflammatory markers, including CD11b, MMP-9 and IL-6, and heightened the endogenous levels of PACAP and its preferring receptor PAC1. Co-treatment with PACAP or VIP prevented rotenone-induced increase of NO, CD11b, MMP-9 and IL-6. These results indicate that both PACAP and VIP are able to prevent the pro-inflammatory effects of rotenone in BV2 cells, supporting the idea that these molecules can have therapeutic value in slowing down PD progression., (© 2022. The Author(s).)

In February 2012 the Rondegat River, in the Cape Floristic Region, was the first river in South Africa where the piscicide rotenone was used to remove an alien invasive fish, smallmouth bassMicropterus dolomieu. In preparation for this treatment, the sensitivity of smallmouth bass to various concentrations of the rotenone formulation CFT Legumine (5% active rotenone) was evaluated a week prior to treatment using standard toxicity tests to determine the minimum effective dose (MED) that would result in 100% mortality after exposure for 4 h. The MED was 0.0125 mg l-1rotenone. Adverse effects, including erratic swimming, loss of equilibrium and death, occurred in a dose-dependent manner with smaller fish responding faster than larger ones. Standard operating procedures for the use of rotenone recommend treatment at a minimum of twice the calculated MED. Given the uncertainty associated with rotenone losses through hydrolysis and photolysis under field conditions, and the possible occurrence of smallmouth bass more tolerant than those tested, a concentration of twice the recommended treatment dose (0.050 mg l-1rotenone) was finally used to treat the Rondegat River for a duration of 6 h. [ABSTRACT FROM PUBLISHER]

Current treatments for Parkinson's Disease (PD) only provide symptomatic relief; however, they don't delay the disease progression, hence new treatment options should be considered. Carvedilol is a nonselective β & α1 blocker with additional effects as an antioxidant, anti-inflammatory and neuro protective properties. In this research, an insilico study was conducted to primarily evaluate carvedilol as an anti-parkinsonian and anti-tau protein target. PASS prediction was performed followed by a docking study of carvedilol. Carvedilol yielded promising results and forward guided this study onto its in vivo evaluation. The in vivo study aimed to assess the neuro-protective effects of carvedilol in rotenone-induced rat model of PD and investigate the potential underlying mechanisms. The effects of carvedilol (2.5, 5, and 10 mg/kg) on the measured parameters of open field, catalepsy, Y-maze tests as well as brain histology, and tyrosine hydroxylase (TH) were evaluated. The effective doses (5 and 10 mg/kg) were further tested for their potential anti-tau protein effects. Carvedilol (5 and 10 mg/kg) prevented rotenone-induced motor deficits, spatial memory dysfunction, and histological damage. Additionally, carvedilol significantly inhibited rotenone-induced decrease in TH expression in the striata of the rats. These effects were associated with reduction of rotenone-induced neuro-inflammation, microglial activation and release of glial fibrillary acidic protein (GFAP), along with reduction in N-methyl-D-aspartate receptors activation, alpha-synculein and phospho-Tau (P-Tau) protein expression. Carvedilol also reduced tau protein hyper-phosphosrylation by Glycogen synthase 3β (GSK 3β) inhibition and Phosphoinositide 3-kinase (PI3K) stimulation. Collectively, these results suggest that carvedilol might be a possible candidate for management of PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Some studies have suggested that mitochondrial dysfunction and a superoxide imbalance could increase susceptibility to chronic stressful events, contributing to the establishment of chronic inflammation and the development of mood disorders. The mitochondrial superoxide imbalance induced by some molecules, such as rotenone, could be evolutionarily conserved, causing behavioral, immune, and neurological alterations in animals with a primitive central nervous system., Objective: Behavioral, immune, and histological markers were analyzed in Eisenia fetida earthworms chronically exposed to rotenone for 14 days., Methods: Earthworms were placed in artificial soil containing 30 nM of rotenone distributed into a plastic cup that allowed the earthworms to leave and return freely into the ground. Since these organisms prefer to be buried, the model predicted that the earthworms would necessarily have to return to the rotenone-contaminated medium, creating a stressful condition. The effect on survival behavior in the immune and histological body wall and ventral nervous ganglia (VNG) structures, as well as gene expression related to inflammation and mitochondrial and neuromuscular changes., Results: Rotenone-induced loss of earthworm escape behavior and immune alterations indicated a chronic inflammatory state. Some histological changes in the body wall and VNG indicated a possible earthworm reaction aimed at protecting against rotenone. Overexpression of the nicotinic acetylcholine receptor gene (nAChR α5) in neural tissues could also help earthworms reduce the degenerative effects of rotenone on dopaminergic neurons., Conclusion: These data suggest that mitochondrial dysfunction could be an evolutionarily conserved element that induces inflammatory and behavioral changes related to chronic stress., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder that occurs after Alzheimer's disease. Rotenone is a neurotoxin commonly used in creating PD models. Safflower (Carthamus tinctorius L.) contains some flavonoids that are effective against neurodegenerative diseases, and it has long been used in the treatment of cerebrovascular diseases in China. In this study, we investigated the preventive effect of safflower standardized flavonoid extract (SAFE) on a rotenone-induced PD rat model. The results showed that SAFE (17.5, 35, or 70 mg kg -1 ·day -1 ) treatment modified the progressive loss in body weight, alleviated behavioral deficits, and promoted survival, especially in the middle-dose SAFE (35 mg kg -1 ·day -1 ) group. SAFE treatment significantly modifies the progressive decrease in the level of DA and its metabolites, DOPAC and HVA, 5-HT and its metabolite 5-HIAA in the St, and levels of TH-positive DA-ergic neurons in the SNpc. SAFE also inhibited the decrease in TH and DA levels and increase in Ach content in the St. SAFE (35 mg kg -1 ·day -1 ) group treatment modifying the rotenone-induced downregulation of JAK2, STAT3, and ɑ7-nAChR, and also modifying the increase in ACh in the hippocampus. SAFE preventive treatment can also partially inhibit changes in the ECS parameters associated with PD. The marker components of SAFE such as Kaempferol 3-O-rutinoside or anhydrosafflor yellow B can bind with TH, JAK2, STAT3, and ɑ7-nAChR based on molecular docking analyses. Current studies have shown that SAFE is a potential candidate for the prevention of PD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gastrointestinal symptoms are common in the early-stage Parkinson's disease (PD), but its potential pathogenesis remains unclear. Therefore, in the present study, we used the 16S ribosomal RNA gene sequencing and gas chromatography coupled with mass spectrometry-based metabolomics to investigate the alterations of gut microbiome and serum amino acid levels in the early-stage PD mice model induced with rotenone. The results demonstrated that the microbial taxa at phylum, family and genus levels remarkably altered in rotenone-induced mice relative to vehicle-induced mice. The rotenone-induced mice had higher relative abundance of Flavobacteriaceae, Staphylococcaceae, and Prevotellaceae as well as lower relative abundance of Lachnospiraceae&#95;UCG-001, Ruminiclostridium, and Prevotellaceae&#95;NK3B31&#95;group than vehicle-induced mice. The evaluation of serum amino acids revealed the alterations in several classes of amino acids, including L-proline, L-alanine, L-serine, L-asparagine, L-threonine, L-glutamine, L-methionine, and L-4-hydroxyproline. Notably, the altered serum amino acid levels were significantly associated with the abundance of gut microbiota, especially Ruminococcaceae and Ruminiclostridium. Our study explored the possible role of the gut-microbiota-metabolite axis in the early-stage PD and provided the possibility of prevention and treatment of PD by gut-microbiota-metabolite axis in the future., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Various studies suggested that neuroinflammation leads to the development of several neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Rotenone is an organic pesticide and potent inhibitor of complex I of electron transport chain widely used to develop the PD model. Numerous studies reported rotenone toxicity in the dopaminergic system but very few studies are available on rotenone-induced glial cell activation and subsequent neurodegeneration and alterations in various types of behavior. Therefore, the present study was designed to explore the effect of rotenone on neuroinflammation and its deleterious effect on the behavior of mice, and also how these effects can be protected through quercetin. Quercetin, a natural flavonoid having strong antioxidant and anti-inflammatory properties, is found in vegetables and fruits. The finding of the study indicated that rotenone 5 mg/kg body weight for 60 days through oral gavage leads to the release of inflammatory markers in blood serum, astrocytes activation in substantia nigra and hippocampus, and subsequently decreased density of dopaminergic fibers in the striatum. Rotenone also altered the memory of the mice as indicated by decreased spontaneous alteration in Y-maze and T-maze tests and reduction in exploration time in novel object recognition, increased immobility time in the forced swim test and reduced muscular strength. Co-treatment of quercetin 30 mg/kg/day through oral gavage for 60 days along with rotenone significantly reversed all these adverse effects, suggesting that quercetin could reduce neuroinflammation, and improve memory, and cognitive function., (© 2022 Wiley Periodicals LLC.)

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.

Asymptomatic and early clinical stages of Parkinson's disease (PD) have been linked with comorbid non-motor symptoms including dysfunction of the gastrointestinal (GI) tract. Notwithstanding, neuroprotective and gastroprotective effects of Ginkgo biloba supplements (GBS) have been investigated independently. Hence, whether GBS-mediated GIT-protective capacity could be helpful in PD via gut-brain anti-inflammatory signaling still remains unknown. Treatment with GBS significantly repressed the motor behavioral and neuromuscular deficits and prevented loss of striatal dopaminergic loss by improving the level of tyrosine hydroxylase enzyme and suppressing synucleinopathy development. Striatal neurons and ileal epithelial injury following intraperitoneal rotenone administration were accompanied with oxidoinflammatory/nitroinflammatory stress and marked inhibition of cholinergic transmission. Moreover, there was increased striatal executioner caspase-3 and decreased nuclear factor erythroid-2-related factor 2 (Nrf2) immunoexpression, loss of striatal pyramidal neuron with a marked decrease in length and width of the dendritic spines as well as significant hyperplasia of cryptal cells in the ileal epithelial tissues, all which were reversed by the pretreatment + concurrent (Pre-CONC) and concurrent (CONC) GBS treatment pattern. In sum, we proved the potential dual effects of GBS in preventing both dopaminergic neural-related impairments and gut wall abnormalities linked with PD., (© 2022 Wiley Periodicals LLC.)

Rosmarinic acid (RA) is a natural polyphenolic compound with antioxidative property. With the present study, we aimed to evaluate the neuroprotective role of RA on Parkinson's disease using rotenone induced SH-SY5Y cell model of Parkinson's disease, the underlying mechanism of action of RA was also investigated. Cell viability, cell morphology, apoptosis, signaling protein phosphorylation and expression, cellular reactive oxygen species (ROS) production, ATP content, and mitochondrial membrane potential were tested in SH-SY5Y cells. RA showed a neuroprotective effect in a rotenone-induced SH-SY5Y cell model of Parkinson's disease with dose-dependent manner, it reduced cell apoptosis and restored normal cell morphology. RA not only decreased levels of α-synuclein and Tau phosphorylation but also elevated the contents of AMPK phosphorylation, Akt phosphorylation, and PGC-1α. RA restored the reduced mitochondrial membrane potential and ATP content as well as inhibited rotenone-induced ROS overproduction. Further findings demonstrated that the neuroprotective role of RA was partially due to the inhibition of Abl tyrosine kinase. RA treatment suppressed the hyperphosphorylation of Abl Y412 and CrkII Y221 induced by rotenone. Nilotinib, a specific inhibitor of Abl, elicited a similar neuroprotective effect as that of RA. The present study indicates that RA has a property of neuroprotection against rotenone, and the neuroprotective effect is partially attributed to the inhibition of Abl.

The development of neuroprotective drugs targeting mitochondria could be an important strategy in combating the progressive clinical course of Parkinson's disease. In the current study, we demonstrated that in SH-SY5Y cells (human dopaminergic neuroblastoma cell line), rotenone caused a dose-dependent (0.25-1 μM) and time-dependent (up to 48 h) loss of cell viability and a loss of cellular ATP content with mitochondrial membrane depolarization and an increased formation of reactive oxygen species; all these processes were markedly prevented by the mitochondrial permeability transition pore blocker cyclosporine A, which did not affect complex I inhibition by rotenone. The nuclear morphology of rotenone-treated cells for 48 h indicated the presence of both necrosis and apoptosis. We then examined the effects of cyclosporine A on the rotenone-induced model of Parkinson's disease in Wistar rats. Cyclosporine A significantly improved the motor deficits and prevented the loss of nigral dopaminergic neurons projecting into the striatum in rotenone-treated rats. Being a marketed immuno-suppressive drug, cyclosporine A should be further evaluated for its putative neuroprotective action in Parkinson's disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting both motor and non-motor functions. It is well reported that the neuropathological process leading to PD starts from the gut before spreading to the CNS affirming the role of environmental toxicants such as rotenone. Morin (3, 5, 7, 2', 4'-pentahydroxyflavone) possesses neuroprotective and anti-oxidant activities which could be beneficial in PD. This study was designed to investigate the ameliorative influence of morin on rotenone-induced PD in mice. Male albino mice (18-23 g) were randomly divided into groups (n = 15) and treated for 28 consecutive days as follows: group 1: normal saline (10 ml/kg, p.o); group 2: rotenone (1 mg/kg, p.o, 0.5%w/v in CMC); groups 3-5: morin (5, 20 or 80 mg/kg, i.p.) + rotenone (1 mg/kg, p.o.), respectively, group 6: morin (20 mg/kg only, i.p.). Behavioural tasks were carried out weekly 1 h after treatments. Mice were euthanized on day 28 and discreet brain regions were assayed for oxidative stress parameters and immunohistochemical analysis. Morin reversed rotenone-induced behavioural deficits (motor incoordination, working memory deficit and depressive-like behaviour). Moreso, rotenone-induced lipid peroxidation (MDA), with a concomitant decrease in glutathione (GSH), superoxide dismutase (SOD) and acetylcholinesterase (AchE) activities in discreet regions of the brain were attenuated by the pre-treatment of mice with morin. Rotenone caused significant increase in the expression of iba-1, glial fibrillary acidic protein (GFAP), toll-like receptor 4 (TLR-4), and α-synuclein with a decrease in tyrosine hydroxylase positive neurons (TH) expression which were ameliorated by the pretreatment of mice with morin. Furthermore, rotenone-induced colon necrosis was reversed by morin administration. This study lend credence to the neuroprotective action of morin on rotenone-induced PD through enhancement of antioxidant defense and anti-inflammatory mechanisms., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Oxidative stress is common to multiple cell death pathways, including apoptosis. We recently identified several compounds that protect against ferroptosis, another cell death pathway associated with oxidative stress, suggesting potential efficacy against apoptosis. The present study assessed the protective efficacies of the ferroptosis inhibitors oxindole-curcumin hybrid compound GIF-2165X-G1, N,N-dimethylaniline derivatives GIF-2014 and GIF-2115, and ferrostatin-1 against rotenone-induced apoptosis. Treatment of mouse hippocampal HT22 cells with the mitochondrial transport chain inhibitor rotenone for 24 h reduced mitochondrial membrane potential, increased reactive oxygen species production, promoted nuclear fragmentation, and ultimately impaired cell viability, consistent with apoptosis. Ferroptosis inhibitor cotreatment did not prevent any of these rotenone-induced apoptotic processes but did suppress delayed cell death associated with loss of plasma membrane integrity. These results suggest that GIF-2165X-G1, GIF-2014, GIF-2115, and ferrostatin-1 are selective for ferroptosis and do not affect apoptosis. Thus, erastin-induced ferroptosis and rotenone-induced apoptosis are distinct cell death pathways despite the common involvement of mitochondrial oxidative stress. Further, the cytoprotective efficacies of chemical antioxidants may depend on the specific source of oxidative stress., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Current treatment of Parkinson's disease (PD) ameliorates symptoms but fails to block disease progression. This study was conducted to explore the protective effects of SVHRSP, a synthetic heat-resistant peptide derived from scorpion venom, against dopaminergic neurodegeneration in experimental models of PD. Results showed that SVHRSP dose-dependently reduced the loss of dopaminergic neuron in the nigrostriatal pathway and motor impairments in both rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse PD models. Microglial activation and imbalance of M1/M2 polarization were also abrogated by SVHRSP in both models. In rotenone-treated primary midbrain neuron-glial cultures, loss of dopaminergic neuron and microglial activation were mitigated by SVHRSP. Furthermore, lipopolysaccharide (LPS)-elicited microglial activation, M1 polarization and related dopaminergic neurodegeneration in primary cultures were also abrogated by SVHRSP, suggesting that inhibition of microglial activation contributed to SVHRSP-afforded neuroprotection. Mechanistic studies revealed that SVHRSP blocked both LPS- and rotenone-induced microglial NADPH oxidase (NOX2) activation by preventing membrane translocation of cytosolic subunit p47phox. NOX2 knockdown by siRNA markedly attenuated the inhibitory effects of SVHRSP against LPS- and rotenone-induced gene expressions of proinflammatory factors and related neurotoxicity. Altogether, SVHRSP protects dopaminergic neurons by blocking NOX2-mediated microglial activation in experimental PD models, providing experimental basis for the screening of clinical therapeutic drugs for PD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Activation of nuclear factor erythroid 2 related factor 2 (Nrf2) associated with the suppression of various oxido-inflammatory pathways and the controller of several gene expressions involving "antioxidant response elements" (AREs) in their promoters to mediate and restores homeostatic functions is now considered as one of the main switch regulating the immune response, and it is also now involved in inflammatory cascade in PD. Whether therapeutic approach using Ginkgo biloba would have significant protective effects against cortico-cerebellar dopaminergic degeneration in rotenone-induced mice remains unknown. In this present study, we studied the therapeutic effects of Ginkgo biloba-supplement (Gb-S) administration in cortico-cerebellar dopaminergic degeneration. The results revealed that treatment with Gb-S suppresses cognitive decline and neuromuscular incompetence in the mice, abated tyrosine hydroxylase depletion and synucleinopathy development in the cortico-cerebellar neurons of the mice before and after rotenone induction. However, our data further shows increase Nrf2 immunoexpression with decrease oxido-nitrergic and neuroinflammatory release, increase cholinergic enzyme activity and downregulated executioner caspase-3 that may mediate cortico-cerebellar apoptosis. Also, the loss of cortico-cerebellar neurons was attenuated, marked by increase in dendritic spine length and width with numerous viable neurons. Overall findings suggest that Gb-S could be a potential pharmacotherapeutic candidate providing a strong protection for cortico-cerebellar neurocellular substances and against Parkinsonism-like non-motor and motor symptoms., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Empagliflozin, a selective sodium-glucose co-transporter-2 inhibitor, has been demonstrated to provide additional non-glycemic benefits, including neuroprotection. Endoplasmic reticulum (ER) stress is a key player in neurodegeneration and occurs at the crossroads of other pathologic mechanisms; however, its role in the pathogenesis of Parkinson's disease (PD) is still elusive. miR-211-5p regulates neuronal differentiation and viability and was predicted to target CHOP, a downstream effector in the ER stress pathway. For the first time, this study investigated the possible neuroprotective effect of empagliflozin in a rotenone-induced rat model of PD from the perspective of ER stress. Rotenone (1.5 mg/kg) was administered subcutaneously every other day for 3 weeks. Meanwhile, the treated group received empagliflozin 10 mg/kg/day orally for 15 consecutive days post-PD induction. On the molecular level, the ER stress pathway components; GRP78, total and phosphorylated PERK, eIF2α and CHOP, along with miR-211-5p expression were upregulated in the striatum of rotenone-injected rats. Concurrently, the untreated rats showed elevated striatal α-synuclein levels along with diminished autophagy and the proteasome system as evidenced by reduced beclin-1 protein and ELF2/NERF mRNA expression levels. The rotenone-induced striatal oxidative stress and neuroinflammation were expressed by reduced catalase activity and elevated interleukin (IL)-1β levels. miR-211-5p was positively correlated with PERK/eIF2α/CHOP, IL-1β and α-synuclein, while negatively correlated with ELF2/NERF, beclin-1 and catalase activity. Empagliflozin treatment showed a restorative effect on all biochemical alterations and improved the motor function of rats tested by open field, grip strength and footprint gait analysis. In the histopathological examination, empagliflozin increased the intact neuron count and attenuated astrogliosis and microgliosis by reducing the glial fibrillary acidic protein and ionized calcium-binding adaptor protein 1 immunostaining. Conclusively, these results emphasize the neurotherapeutic impact of empagliflozin in PD by moderating the GRP78/PERK/eIF2α/CHOP ER stress pathway, downregulating miR-211-5p, resolving oxidative stress, lessening astrocyte/microglial activation and neuroinflammation, along with augmenting autophagy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

More and more reports have pointed out that rotenone, as an insecticide, has high neurotoxicity and reproductive toxicity to livestock and mammals. As a highly physiological correlation system of internal organs, quasi-organs have great potential in the fields of drug toxicity and efficacy test, toxicology research, developmental biology and so on. In this study, brain organs (mBOs) derived from mouse neural stem cells were used to investigate the effects of rotenone on the physiological activity and epigenetic modification of mBOs. At the same time, Rotenone could significantly stimulate the increase of the concentration of LPO, lactic acid and hydroxyl radical in mBOs, and inhibit the expression of neuronal marker Tuj1, CHAT, PAX6 and so on. Further analysis showed that Rotenonem could induce mitochondrial damage in mBOs. The results of qPCR and Western blot showed that Rotenone could up-regulate the expressions of ferroptosis promoting protein p53, Cox2 and so on, while inhibit the expressions of negative regulatory protein of ferroptosis GPX4, FTH1, SLC7A11. In addition, the results of RRBS-Seq sequencing showed that the methylation modification at DMR level in Rotenone-treated mBOs group was significantly higher than that in Ctrl group. The results of KEGG analysis showed that compared with Ctrl, the genes with hypermethylation of promoter and Genebody in Rotenone-treated mBOs were mainly located in the Neuro active ligand-receptor interaction signal transduction pathway. In summary, rotenone can significantly lead to abnormal methylation of mouse brain organs, and lead to the loss of normal physiological function of neurons by inducing ferroptosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)