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Ethnopharmacological Relevance: Cajanus cajan (L) Millsp (Fabaceae) seed decoction is used by traditional healers in Nigeria as nerve tonic, hence, could be beneficial in the treatment of Parkinson's disease (PD), a progressive and debilitating neurodegenerative disease that imposes great burden on the healthcare system globally., Aim of the Study: This study aimed at investigating the neuroprotective effect of ethanol seed extract of Cajanus cajan (CC) in the treatment of rotenone-induced motor symptoms and non-motor symptoms associated with PD., Materials and Methods: To assess the protective action of CC on rotenone-induced motor- and non-motor symptoms of PD, mice were first pretreated with CC (50, 100 or 200 mg/kg, p.o.) an hour before oral administration of rotenone (1 mg/kg, p.o, 0.5% in carboxyl-methylcellulose) for 28 consecutive days and weekly behavioural tests including motor assessment (open field test (OFT), rotarod, pole and cylinder tests) and non-motor assessment (novel object recognition (NOR), Y-maze test (YM), forced swim and tail suspension, gastric emptying and intestinal fluid accumulation tests) were carried out. The animals were euthanized on day 28 followed by the collection of brain for assessment of oxidative stress, inflammatory markers and immunohistochemical analysis of the striatum (STR) and substantia nigra (SN). Phytochemicals earlier isolated from CC were docked with protein targets linked with PD pathology such as; catechol-O-methyltransferase (COMT), tyrosine hydroxylase (TH) and Leucine rich receptor kinase (LRRK)., Results: this study showed that CC significantly reduced rotenone-induced spontaneous motor impairment in OFT, pole, cylinder and rotarod tests in mice as well as significant improvement in non-motor features (significant reversal of rotenone-induced deficits discrimination index and spontaneous alternation behaviour in NORT and YM test, respectively, reduction in immobility time in forced swim/tail suspension test, gastrointestinal disturbance in intestinal transit time in mice. Moreso, rotenone-induced neurodegeneration, oxidative stress and neuroinflammation were significantly attenuated by CC administration. In addition, docking analysis showed significant binding affinity of CC phytochemicals with COMT, TH and LRRK2 receptors., Conclusion: Cajanus cajan seeds extract prevented both motor and non-motor features of Parkinson disease in mice through its antioxidant and anti-inflammatory effects. Hence, could be a potential phytotherapeutic adjunct in the management of Parkinson disease., 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.)

Background: Smoking is associated with dysregulation of the antioxidant system and addiction., Aim: This study sought to ascertain the effect of Nigella Sativa (NS) oil on the antioxidant system, nicotine/tobacco addiction as well as the expressions of α4β2 nicotinic (nAChR) and dopamine type-2 (DRD2) receptors in selected brain regions of the rat., Methods: Thirty male Sprague-Dawley rats were divided into 6 groups comprising of vehicle-treated control, NS oil only, Smoke only, Smoke + NS oil, Nicotine only and Nicotine + NS oil. Animals were passively exposed to cigarette smoke or nicotine vapour for 12 weeks, however, NS oil treatment commenced from 9th-12th week of the experimental duration., Results: Nicotine vapour and cigarette smoke-induced increase in cotinine level were significantly ameliorated by NS treatment. Cigarette smoke or nicotine vapour exposure significantly (p<0.05) decreased the level of antioxidant enzymes while increasing malondialdehyde level in the brain homogenates of the rats.  Administration of NS oil significantly (p<0.05) reversed the reduced antioxidant level. Cigarette-smoke also significantly increased α4-nAChR expression in the frontal cortex and olfactory bulb compared to control. Nicotine vapour significantly increased DRD2 expression only in the olfactory cortex. NS oil administration reduced both the cigarette-smoke-induced increase in α4-nAChR and nicotine vapour-induced increase in DRD2 gene expression only in the olfactory cortex., Conclusion: Findings from this study suggest that NS oil improves brain antioxidant status while ameliorating nicotine vapour and cigarette smoke addiction through down-regulation of α4-nAChR and DRD2 gene expressions in discrete brain regions in Sprague-Dawley rats.

Introduction: Globally, the incidence of inflammation and inflammatory disorders has continued to rise at an alarming rate. Entandrophragma utile is a species of flowering plant widely distributed in Africa and has been used for the management of sickle cell disease, rheumatism, ocular inflammation, duodenal and stomach ulcers. This research aims to formulate and evaluate an anti-inflammatory herbal emulgel using an extract from Entandrophragma utile stem bark (EUB). Method: Using a carrageenan-induced paw oedema model, the anti-inflammatory efficacy of EUB the extract was assessed. The formulated Entandrophragma utile emulgels (EUE) were characterized, and their anti-inflammatory activity was demonstrated, by utilizing diclofenac emulgel-treated rats with complete Freund's adjuvant (CFA)-induced arthritis model as the positive control group. Results: The emulgels formulated had characterization results within acceptable ranges; pH (4.25-5.80), viscosity (418.9-112.8 mPas), spreadability (25.00-31.82 gcm/s), extrudability (30.86-51.02 g/cm 2 ), and a swelling index of (30-60%). The emulgel produced a concentration-dependent inflammatory inhibition with a peak effect (117.97%) at the end of the 4th week which was comparable to that of commercial diclofenac (127.19%). The phytochemical analysis led to the identification of saponins, flavonoids, phenols, and tannins as active secondary metabolites. Conclusions: The stem bark extract of E. utile possessed noteworthy ( p < 0.05) reduction in inflammation in comparison to diclofenac and its emulgel formulation showed enormous potential for treating inflammation and pain.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16.  The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action.  pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

It is well established that there is a link between type 2 diabetes mellitus and Parkinson's disease (PD) evidenced in faster progression and more severe phenotype in patients living with diabetes suggestive of shared cellular pathways; hence, antidiabetic drugs could be a possible treatment options for disease modification. This study evaluated the effect of glimepiride (GMP), a third generation sulphonylurea, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Sixty mice were divided randomly into six individual groups of 10 mice each and dose orally as follows: group 1: vehicle (10 ml/kg, p.o.); group 2: MPTP (20 mg/kg, i.p. × 4 at 2-h interval); groups 3-5: GMP (1, 2, or 4 mg/kg, p.o.) + MPTP (20 mg/kg, i.p. × 4 at 2-h interval); and group 6: GMP (4 mg/kg, p.o.). Effect of glimepiride on motor activities were appraised with the use of open-field test and rotarod performance while non-motor activity was evaluated using force swim test (FST; depression) and Y-maze test (working memory). MPTP induced significant decrease in latency to fall on rotarod, distance covered/rearing in open field, mean speed and climbing in FST, and percentage alternation behavior in Y-maze suggestive of motor and non-motor dysfunction. However, MPTP-induced motor and non-motor dysfunction were ameliorated with glimepiride post-treatment. In addition, MPTP-induced increase in oxidative stress parameters and cholinergic neurotransmission was attenuated by glimepiride. In addition, MPTP-induced nigral dopamine neuron loss (decrease in tyrosine hydroxylase-positive neuron (TH)) and neuroinflammation (activation of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (iba-1)) were ameliorated by GMP administration. This study showed that glimepiride ameliorates MPTP-induced PD motor and non-motor deficits through enhancement of antioxidant defense signaling and attenuation of neuroinflammatory markers. Thus, this could be useful as a disease-modifying therapy in the management of PD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Epidemiological reports showed a significant association between environmental toxicants-induced gut dysbiosis and PD. Neuroinflammation, mitochondrial dysfunction and decreased cerebral blood flow are hallmarks of PD. This study sought to evaluate the protective ability of vinpocetine (VIN), a neuroprotectant, on rotenone (ROT) (mitochondrial complex I inhibitor) induced PD in rats. Sixty male Sprague Dawley rats were randomly divided into six groups (n = 10) and treated orally as follows; group 1: vehicle (10 ml/kg); group 2: rotenone (10 mg/kg) + vehicle; group 3-5: vinpocetine (5, 10 or 20 mg/kg) + rotenone (10 mg/kg), respectively, or group 6: vinpocetine 20 mg/kg before behavioural assay for motor symptoms (fore-limb hanging test and open field test) and non-motor symptoms (working memory and learning capabilities in Y-maze/Morris water maze tasks, anxiety in hole board test and gut motility with intestinal transit time). Following treatment for 28 days, biochemical assays and immunostaining was performed. We examined the effect of vinpocetine on rotenone-induced oxidative stress and inflammatory markers. The pretreatment of rats with vinpocetine reversed rotenone-induced locomotor deficit, motor incoordination, cognition deficits and gut dysfunction. In addition, rotenone-induced a significant increase in the level of interleukin-6 and tumor necrotic factor-α, oxidative stress markers, cholinergic signalling, gut dysfunction and haematologic dysfunctions which were attenuated by vinpocetine administration. Immunostainings showed that rotenone-induced dopamine neuron loss, microglia reactivity, astrocytes activation, toll-like receptor 4 (TLR4) and α-synuclein (SNCA) expressions which were attenuated by vinpocetine administration. Findings from this study revealed a neuroprotective effect of vinpocetine on rotenone-induced PD through anti-neuroinflammatory and antioxidant mechanisms., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ishola Ismail Ogunbayode reports financial support was provided by international society of neurochemistry., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The seeds of Cajanus cajan (L) Millsp, are used in Traditional medicine for the treatment of anxiety and other neurological disorders. Hence, this study is designed to investigate the antidepressant- and anxiolytic-like properties of ethanol seed extract of Cajanus cajan (CC) in mice., Materials and Methods: CC (50, 100 or 200 mg/kg, p.o.) was administered 1h before subjecting the animals to different behavioral models: forced swim test (FST) and tail suspension test (TST) (depressive-like behaviour), open field test (OFT), elevated plus maze (EPM), light-dark test (LDT) and hole-board test (HBT) for anxiety-like behaviour. To ascertain the pharmacodynamic of CC mice were pretreated with monoaminergic, nitrergic and GABAergic receptors antagonists. As well as molecular docking analysis of about 19 flavonoids present in CC on GABA A , α 2 adrenoceptors and 5-HT 2A receptors., Results: CC (50, 100 or 200 mg/kg, p.o.) treatment significantly reduced immobile time in both FST and TST when compared with vehicle-treated control. However, the pretreatment of mice with prazosin/yohimbine (α 1/2 adrenoceptor antagonists, respectively), WAY100635 (5-HT 1A receptor antagonist), ketanserin (5-HT 2A receptor antagonist), sulpiride (dopamine D 2 receptor antagonist), L-N G -Nitro arginine methyl ester (L-NAME), or methylene blue reversed the antidepressant-like effect of CC. In anxiety model, CC produced significant (p < 0.05) increase in open arms exploration and head dipping behavior which was reversed by flumazenil (benzodiazepine receptor antagonist) in the EPM. Docking analysis showed significant binding affinity of orientin, vitexin, pinostrobin and quercetin with 5HT 2A , α 2 -adrenoceptor and GABA A receptors., Conclusion: Findings from this study showed that C.cajan seeds extract exerts antidepressant-like effect through participation of monoaminergic systems (5-HT 2 receptor, α 1 /α 2 -adrenoceptors, and dopamine D 2 -receptors), nitric oxide-cyclic GMP pathway and anxiolytic-like effect via GABA A benzodiazepine receptors. Moreso, presence of flavonoids with significant binding energies with monoaminergic and GABAergic systems support the potential of the extract in the management of mixed anxiety-depressive illness., Competing Interests: Declaration of competing interest We do not have any conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor features. The current treatment regimen for PD are dopamine enhancers which have been reported to worsen the disease prognosis after long term treatment, thus, the need for better treatment options. This study sought to investigate the protective action of Double Stem Cell® (DSC), a blend of stem cells extracts from Swiss apples (Malus Domestica) and Burgundy grapes (Vitis vinifera) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice and genetic model of PD in Drosophila melanogaster. Male albino mice were pretreated with MPTP (4 × 20 mg/kg, i.p., two hourly in 8 h), twelve hours before administration of DSC (8, 40, or 200 mg/kg, p.o.). Thereafter, behavioural, biochemical and immunohistochemical assays were carried out. The impact of vehicle or DSC supplementation on α-synuclein aggregation was evaluated in Drosophila melanogaster using the UAS-Gal4 system, female DDC-Gal4 flies were crossed with male UAS-α-synuclein, the progenies were examined for fecundity, locomotion, memory, and lifespan. MPTP-induced motor deficits in open field test (OFT), working memory impairment (Y-maze test (YMT)) and muscle incoordination (rotarod test) were ameliorated by DSC (8, 40 or 200 mg/kg) through dose-dependent and significant improvements in motor, cognitive and motor coordination. Moreso, MPTP exposure caused significant increase in lipid peroxidation and decrease in antioxidant enzymes activities (glutathione, catalase and superoxide dismutase) in the midbrain which were attenuated by DSC. MPTP-induced expression of microglia (iba-1), astrocytes (glia fibrillary acidic protein; GFAP) as well as degeneration of dopamine neurons (tyrosine hydroxylase positive neurons) in the substantia nigra (SN) were reversed by DSC. Supplementation of flies feed with graded concentration of DSC (0.8, 4 or 20 mg/ml) did not affect fecundity but improved climbing activity and lifespan. Findings from this study showed that Double Stem Cell improved motor and cognitive functions in both mice and Drosophila through attenuation of neurotoxin-induced oxidative stress and neuroinflammation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. This study is aimed at evaluating the effects of Clerodendrum polycephalum (CP) leaf extract on chemical-induced seizures in mice and the possible mechanisms of action. Swiss albino mice were pretreated with CP (50, 100, or 500 mg/kg, p.o.) prior to intraperitoneal injection of picrotoxin (PTX) or pentylenetetrazole (PTZ). However, the most effective dose was used to elucidate the role of GABAergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling mechanisms in mice brains. Accordingly, we evaluated the preventive and reversal effects of CP on kainic acid (KA)-induced temporal lobe epilepsy (TLE), oxidative stress, and neuroinflammatory in mice. The pretreatment of mice with CP delayed the latencies to PTX and PTZ-induced seizures and decrement in the period of tonic-clonic attacks. Interestingly, CP (100 mg/kg) completely prevented PTZ-induced tonic-clonic seizures. Contrastingly, flumazenil (benzodiazepine receptor antagonist), N G -nitro-L-Arginine (L-NNA) (10 mg/kg., neuronal nitric oxide synthase inhibitor), and methylene blue (MB) (2 mg/kg, a soluble guanylyl cyclase inhibitor) but not L-arginine (150 mg/kg., nitric oxide precursor) reversed CP-induced anticonvulsant-like effect in PTZ model. Furthermore, KA-elicited TLE was prevented by CP treatment. CP also attenuated KA-induced oxidative stress, cyooxygenase-2 (COX-2), and nuclear factor kappa-B (NF-κB) elevated expressions in the hippocampus. The study revealed that the ethanolic leaf extract of CP produced anticonvulsant actions through enhancement of antioxidant defense, GABAergic, and NO-cGMP signaling pathways as well as attenuation of inflammatory processes. PRACTICAL APPLICATIONS: The leaves of Clerodendrum polycephalum Baker (Labiatae) are used as a dietary legume supplement and applied ethnomedicinally for the management of epilepsy, convulsion, and spasms. For this reason, we believe that supplementation of the Clerodendrum polycephalum leaf extract would prevent epileptic-related disorders in mice induced with epileptic conditions using kainic acid and other behavioral phenotypic models. Here, our findings clearly revealed that Clerodendrum polycephalum leaf extract protects against conditions of epileptic-related disorders and thus might be relevant as a dietary supplement in the prevention or delay of the onset of seizures and epileptic behavior., (© 2022 Wiley Periodicals LLC.)

In spite of the increasing epidemic of pharmaceutical opioids (codeine and tramadol) misuse and abuse among the adolescents, little is known about the neurotoxic consequences of the widespread practice of tramadol and codeine abuse involving increasing multiple doses across days, referred to as stacking and boosting. Hence, in this study, we replicated stacking and boosting doses of tramadol, codeine alone, or in combination on spontaneous motor activity and cognitive function in adolescent mice and adduced a plausible mechanism of possible neurotoxicity. Ninety-six adolescent mice were randomly distributed into 4 groups (n = 24 per group) and treated thrice daily for 9 days with vehicle, tramadol (20, 40, or 80 mg/kg), codeine (40, 80, or 160 mg/kg), or their combinations. Exposure of mice to tramadol induced hyperactivity and stereotypic behavior while codeine exposure caused hypoactivity and nootropic effect but tramadol-codeine cocktail led to marked reduction in spontaneous motor activity and cognitive function. In addition, tramadol, codeine, and their cocktail caused marked induction of nitroso-oxidative stress and inhibition of mitochondrial complex I activity in the prefrontal cortex (PFC) and midbrain (MB). Real-time PCR expression profiling of genes encoding neurotoxicity (RT) showed that tramadol exposure upregulate 57 and downregulate 16 neurotoxic genes, codeine upregulate 45 and downregulate 25 neurotoxic genes while tramadol-codeine cocktail upregulate 52 and downregulate 20 neurotoxic genes in the PFC. Findings from this study demonstrate that the exposure of adolescents mice to multiple and increasing doses of tramadol, codeine, or their cocktail lead to spontaneous motor coordination deficits indicative of neurotoxicity through induction of oxidative stress, inhibition of mitochondrial complex I activity and upregulation of neurotoxicity encoding genes in mice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gymnosporia heterophylla (synonym Maytenus) is widely used in folk medicine for the treatment of various illness including neurological diseases. This study presents the antidepressant-like and anxiolytic-like effects of novel bioactive constituents; 3,4-seco-1-hydroxy-21-oxoolean-3,11-olide (A2), 1β,2β-diacetoxy-9β-benzoyloxy-6α-nicotinoyloxy-β-dihydroagarofuran (A5) as well as known 3-acetoxy-1β-hydroxyLupe-20(29)-ene (selective COX-2; A4) from the aerial parts of G. heterophylla. The antidepressant-like effect was studied using the forced swim test (FST) while the elevated plus maze test (EPMT) and open field test (OFT) were employed for anxiolytic-like effect. Acute treatment with A4 and A5 (0.5, 5 or 10 mg/kg) significantly reduced the duration of immobility and immobile episodes with prolongation of immobility latency in the FST with peak effects observed at 10 and 0.5 mg/kg, respectively. Moreover, antidepressant-like effect of A4 and A5 were relatively better than that of fluoxetine. Conversely, the pretreatment of mice with prazosin (1 mg/kg, α 1 -adrenoceptor antagonist), yohimbine (1 mg/kg; α 2 -adrenoceptor antagonist), or sulpiride (50 mg/kg; dopamine D 2 -receptor antagonist) reversed antidepressant-like effect of A4 and A5 but not WAY 100635 (10 mg/kg, i.p., selective 5-HT 1A receptor antagonist), GR 127935 (5 mg/kg, i.p., selective 5-HT 1B receptor antagonist), metergoline (4 mg/kg, i.p, non-selective 5-HT 2 receptor antagonist), ketanserin (5 mg/kg, i.p., a selective 5-HT 2A receptor antagonist) or p-chlorophenylalanine (pCPA) (100 mg/kg, i.p., tryptophan hydroxylase inhibitor) in the FST. Interestingly, A2, A4 and A5 significantly increased the time spent in the open arms of the EPM suggestive of anxiolytic-like action. Findings from this study showed that the novel β-dihydroagarofuran sesquiterpene alkaloid and triterpenes possesses antidepressant-like and anxiolytic-like effects through enhancement of monoaminergic signaling., (Copyright © 2022 Elsevier Ltd. 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.)

Parkinson disease (PD) is a major public health challenge as many of the current drugs used in its management provide symptomatic relieve without preventing the underlying cause of the neurodegeneration. Similarly, the non-motor complications of PD, especially the gastrointestinal tract (GIT) disturbance increases the disease burden on both the PD patient and caregivers. Different theories have been postulated regarding the mechanisms or pathways involved in PD pathology but gut-brain axis involvement has gained much more momentum. This pathway was first suggested by Braak and colleagues in 2003, where they suggested that PD starts from the GIT before spreading to the brain. However, human exposure to environmental toxicants known to inhibit mitochondrial complex I activity such as rotenone, paraquat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are well associated with PD. Several reports have shown that oral exposure of laboratory animals to rotenone causes mitochondria dysfunction, GIT disturbance, overexpression of alpha synuclein and microbiota imbalance. This review focuses on the mechanism(s) through which rotenone induces PD pathogenesis and potential for therapeutic small molecules targeting these processes at the earliest stages of the disease. We also focused on the interaction between the GI microbiota and PD pathology., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Epilepsy remains an unmet medical need affecting more than 50 million people worldwide with about 125,000 mortality annually and more prevalent in low- and middle-income countries. Nymphaea lotus (also known as water lilly) is an aquatic plant used traditionally to treat convulsive episodes in Southwestern Nigeria. This study was undertaken to evaluate anticonvulsant activity of aqueous Nymphaea lotus extract (ANL) and ethanol Nymphaea lotus extract (ENL) on chemical-induced seizures in mice as well as possible mechanisms of action. Vehicle (10 mL/kg, p.o.), ANL (50-200 mg/kg, p.o.), ENL (50-200 mg/kg) or diazepam (5 mg/kg, p.o.) was administered 1 h prior to chemo-convulsant (picrotoxin (PCT), pentylenetetrazol (PTZ), strychnine or N-methyl-D-aspartate (NMDA)) administration. Most effective doses of the extracts were administered to mice after the establishment of temporal lobe epilepsy (TLE) induced by kainic acid. Thereafter, memory assessment in Y-maze, depressive-like behaviour in tail suspension test (TST) and anxiety model in elevated plus maze test (EPM). The prefrontal cortex and hippocampus were assayed for oxidative stress parameters. The pretreatment of mice with ANL or ENL significantly prolonged onset of seizures and reduced the duration of picrotoxin-, pentylenetetrazol-, and strychnine-induced seizures or NMDA-induced turning behaviour. Kainic acid induced spontaneous recurrent seizures and oxidative stress were ameliorated by N. lotus extracts. Moreover, N. lotus-induced anticonvulsant action was reversed by the pretreatment of mice with flumazenil (benzodiazepine receptor antagonist) or L-arginine (nitric oxide precursor). In addition, kainic acid induced neurodegeneration was reduced by N. lotus extract. Findings from this study showed anticonvulsant activity of Nymphaea lotus in neurotoxins-induced seizures through enhancement of inhibitory GABAergic/ antioxidant signalling and inhibition of glutamatergic neurotransmission., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: This study sought to investigate the beneficial effect of kolaviron (KV) (a biflavonoid) isolated from Garcinia kola seed on chronic unpredictable mild stress (CUMS)-induced anxiety- and depressive-like behavior., Methods: Male albino mice were randomly divided into six groups (n=8) as follows; Group I: vehicle-control unstressed; Group II: CUMS-control; Group III-V: CUMS + KV 1, 5 or 50 mg/kg, respectively, Group VI: KV (50 mg/kg, p.o.) unstressed mice. Animals were subjected to CUMS for 14 days, followed by estimation of depressive- and anxiety-like behavior from days 14-16. This was followed by biochemical assays for oxidative stress, hypothalamo-pituitary axis, cholinergic, and BDNF signaling., Results: CUMS caused significant reduction in time spent in open arms of elevated plus maze test (EPM) and increase in immobility time in tail suspension test (TST) and forced swim test (FST) ameliorated by KV treatments. KV administration also attenuated CUMS-induced malondialdehyde/nitrite generation and decrease in antioxidant enzymes activities in the prefrontal cortex and hippocampus. CUMS increased serum corticosterone, acetylcholinesterase activity, and reduced BDNF level in the PFC and hippocampus were attenuated by KV administration., Conclusions: KV prevented CUMS induced anxiety- and depression-like behavior in mice through enhancement of antioxidant defense mechanisms, neurotrophic factors, and cholinergic systems., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: This study investigates the influence of Cnestis ferruginea (CF) on kainic acid (KA)-induced immediate early genes (IEGs) associated with hippocampal sclerosis in temporal lobe epilepsy (TLE) in mice., Methods: Animals were randomly divided into preventive treatment; vehicle (10 mL/kg, p.o.) or CF (400 mg/kg, p.o.) for three consecutive days before KA (5 mg/kg, i.p.) on days 4 and 5. In the reversal model, KA (5 mg/kg, i.p.) was administered on days 1 and 2 before CF (400 mg/kg) administration on days 3-5. Animals were euthanized on day 5, 6 h after KA exposure in preventive model and 1 h after CF administration in reversal model to estimate markers of IEGs., Results: KA upregulated the expression of c-Fos protein by 3.32-, 9.45-, 8.13-, and 8.66-fold in the hippocampal CA1, CA2, CA3, and DG regions, respectively. Also, KA elevated inducible nitric oxide synthase protein expression by 10.9-, 10.6-, 9.78-, and 9.51-fold. Besides, mRNA expression of brain-derived neurotrophic factors and heat shock protein was increased by 2.38- and 1.39-fold, respectively, after exposure to KA which were attenuated by CF., Conclusions: CF attenuated KA-induced IEGs and could be used as an adjunct in TLE., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Currently, prevailing evidence have identified cholinergic and oxidative pathways as important therapeutic targets for abating ketamine-induced schizophrenia-like behavior. Thus, this study evaluated the ability of hesperidin, a naturally occurring antioxidant and neuroprotective flavonoid, to prevent and reverse ketamine-induced schizophrenia-like behaviors and changes in cholinergic, oxidative and nitrergic status in mice. Forty-eight male Swiss mice were allotted into the preventive and reversal studies with 4 groups (n = 6) each. In the preventive study, groups 1 and 2 received vehicle (10 mL/kg/p.o./day), while groups 3 and 4 had hesperidin (100 mg/kg/p.o./day) for 14 days, but ketamine (20 mg/kg/i.p./day) was concurrently given to groups 2 and 4 from days 8-14. In the reversal study, groups 1 and 3 received vehicle, groups 2 and 4 were pretreated with ketamine for 14 days. Nevertheless, groups 3 and 4 additionally received hesperidin from days 8-14. Thereafter, schizophrenia-like behavior from exploratory activity, open-field (positive symptoms), Y-maze (cognitive symptoms) and social interaction (negative symptoms) tests were evaluated. Brain levels of oxidative/nitrergic (glutathione, superoxide-dismutase, malondialdehyde and nitrite levels) and cholinergic (acetylcholinesterase activity) markers were measured in the prefrontal-cortex, striatum and hippocampus. Hesperidin prevents and reverses ketamine-induced hyperactivities, social withdrawal and cognitive impairment. Also, hesperidin prevented and reversed ketamine-induced decrease in glutathione and superoxide-dismutase levels in the prefrontal-cortical, striatal and hippocampal brain regions in mice. Consequently, hesperidin attenuated ketamine-induced increase in malondialdehyde, nitrite levels and acetylcholinesterase activities in the prefrontal-cortex, striatum and hippocampus, respectively. The study showed that hesperidin prevents and reverses ketamine-induced schizophrenia-like behavior through inhibition of oxidative/nitrergic stress and acetylcholinesterase activity in mice brains. Therefore, these findings suggest that hesperidin dietary supplementation could provide natural nutritional intervention to protect against epigenetic-induced mental ill-health like schizophrenia, and thus serve as an important agent for nutritional psychiatry., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized by motor and non-motor symptoms due to loss of striatal dopaminergic neurons and disruption of degradation signaling leading to the formation of Lewy bodies (aggregation of α-synuclein). Presently, there are no disease modifying therapy for PD despite improvement in the understanding of the disease pathogenesis. However, the drugs currently used in PD management provide symptomatic relieve for motor symptoms without significant improvement in non-motor complications, thus, a public health burden on caregivers and healthcare systems. There is therefore the need to discover disease modifying therapy with strong potential to halt the disease progression. Recent trend has shown that the dysfunction of lysosomal-autophagy pathway is highly implicated in PD pathology, hence, making autophagy a key player owing to its involvement in degradation and clearance of misfolded α-synuclein (a major hallmark in PD pathology). In this review, we described the current drugs/strategy in the management of PD including targeting the autophagy pathway as a novel approach that could serve as potential intervention for PD management. The discovery of small molecules or natural products capable of enhancing autophagy mechanism could be a promising strategy for PD treatment., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Parkinson's disease (PD) and dementia with Lewy bodies have several commonalities including neurochemical, morphological and clinical features as well as widespread of cortical and limbic α-synuclein and amyloid-β pathologies. Thus, we evaluated the action of hesperidin on α-synuclein and amyloid-β-induced neurodegeneration in Drosophila melanogaster. The disease causing human Aβ peptide or α- synuclein was expressed respectively, in Elav-GAL4 (pan-neuronally) and dopaminergic neurons (ddc-GAL4) using the UAS-GAL4 system. Flies were either grown on food media supplemented with or without hesperidin (HSD) (1, 5, or 10mM). Behavioral assays were carried to investigate the effect of treatment on fecundity, larval motility, climbing ability and lifespan. Aβ>Elav or α-syn>DDC caused significant decrease in fecundity, larva contraction, motility, survival rate, and climbing activities in flies indicative of neurodegeneration. However, supplementation of flies' media with hesperidin (1mM, 5mM and 10mM) showed a dose-dependent increase in the number of line crosses in the egg laying, larva motility, climbing activity in comparison with flies grown on food media only. Conversely, supplementation of fly feed with HSD caused no significant change in lifespan. Findings from this experiment showed that hesperidin could be a potential neuroprotective agent in the amelioration of PD and AD pathogenesis.

Mounting evidences have shown that nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox-2) pathway modifies glutamic-acid decarboxylase-67 (GAD 67 ) (GABAergic enzyme) and cholinergic systems via oxidative-nitrergic mechanisms in schizophrenia pathology. Rutin, a neuroactive antioxidant compound, with proven neuroprotective property has been shown to reduce schizophrenic-like behavior in mice. This study sought to investigate the mechanisms of action of the psychopharmacological activity of rutin in the preventive and reversal effects of ketamine-induced schizophrenic-like behavior, oxidative-nitrergic stress, cholinergic and GABAergic derangements in mice. In the preventive treatment, male mice were given rutin (0.1, 0.2 and 0.4 mg/kg) or risperidone (0.5 mg/kg) orally for 14 days prior to ketamine (20 mg/kg, i.p.) treatment from the 8 to 14th day. However, in the reversal treatment, ketamine was given for 14 days prior to rutin and risperidone. Behavioral (open-field, social-interaction and Y-maze tests), biochemical (oxidative/nitrergic stress markers, acetylcholinesterase activity), immunohistochemical (GAD 67 , Nox-2) and neuronal cell deaths in the striatum, prefrontal cortex, and hippocampus were evaluated. Ketamine-induced behavioral impairments were prevented and reversed by rutin. Exposure of mice to ketamine increased malondialdehyde, nitrite contents, acetylcholinesterase activity, neuronal cell death and Nox-2 expressions in the striatum, prefrontal cortex and hippocampus. Conversely, these derangements were prevented and reversed by rutin. The decreased glutathione levels due to ketamine were marked increased by rutin. Rutin only prevented ketamine-induced decrease in GAD 67 expression in the striatal-hippocampal region. Altogether, the study showed that the prevention and reversal treatments of mice with rutin attenuated ketamine-induced schizophrenic-like behaviors via reduction of Nox-2 expression, oxidative/nitrergic stresses, acetylcholinesterase activity, and increased GAD 67 enzyme.

Vinpocetine has been shown to protect against degenerative senile cerebral dysfunction via enhancement of cerebral blood flow, cognition and neuroprotective action. This study sought to investigate the protective effect of vinpocetine against haloperidol-induced catalepsy in mice. Vinpocetine (5, 10 or 20 mg/kg, p.o.) was administered 1 h after haloperidol injection for 21 consecutive days. Effect on motor coordination, depressive-like behaviour and working memory were assessed with rotarod, forced swim (FST) and Y-maze tests, respectively. Brains were collected on day 21 for biochemical estimation of nitrosative and oxidative stress parameters. Vinpocetine (10 or 20 mg/kg, p.o.) significantly reversed haloperidol-induced motor deficit in rotarod test and open field test and reduced the duration of catalepsy during acute and chronic catalepsy tests as compared to trihexylphenidyl but failed to reverse haloperidol-induced memory deficit in the Y-maze test. Haloperidol-induced increase in malondialdehyde and nitrite generation as well as deficits in antioxidant enzymes activities were attenuated by chronic administration of vinpocetine. These findings suggest that vinpocetine protects against haloperidol-induced catalepsy and motor deficits through attenuation of oxidative/nitrosative stress.

Objectives: Concurrent use of herbs with drugs have become a major healthcare problem. Herb-drug interactions could lead to therapeutic failure or toxicity. Hence, this study seeks to evaluate the impact of combining Curcuma longa rhizome (CL) with selected anxiolytic and hypnotic drugs., Methods: CL (100, 200 or 400 mg/kg, p.o.) was administered to mice 1 h before subjecting the animals to elevated plus maze (EPM), hole board test (HBT), open field test (OFT) and rotarod test for anxiolytic-like effect as well as hexobarbitone-induced sleeping time (HIST) for hypnotic activity. The involvement of GABAergic and nitrergic systems in CL-induced anxiolytic and hypnotic actions were also evaluated. The effect of concurrent use of CL with midazolam, imipramine, nifedipine, propranolol and carbamazepine were evaluated in anxiolytic-hypnosis models., Results: The peak anxiolytic-like effect of CL was obtained at 400 mg/kg in the EPM and hole-board test without affecting muscle coordination in the rotarod test while the peak hypnosis-potentiation was observed at 100 mg/kg. CL-induced anxiolytic-hypnotic-like effects were reversed by the pretreatment of mice with flumazenil or N G -nitro-l-arginine., Conclusions: Curcuma longa possesses anxiolytic and hypnotic effects through its interaction with GABAergic and nitrergic systems. Conversely, co-administration of C. longa with midazolam potentiate barbiturate-induced hypnosis., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Prenatal exposure to valproic acid (VPA) has been shown to increase the risk of autism in children. This study examined the effect of metformin on VPA-induced autism spectrum disorders in rats. Pregnant albino rats administered VPA (500 mg/kg, i.p.) or normal saline (10 mL/kg, i.p.; vehicle-control) on gestational day 12.5. The pups were given metformin (5, 50 or 500 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) daily from postnatal day (PND) 21-50. Social behaviour, spatial learning/reference memory, repetitive behaviour and anxiety were assessed using the three-chamber social assay, Morris water maze (MWM), Y maze and elevated plus maze tests (EPM), respectively. On PND 51, the animals were euthanized and brains removed for biochemical assay. In utero VPA exposure caused significant reduction in sociability index, social novelty preference index in three-chambered apparatus and spatial learning and reference memory deficits in the MWM task as well as increase in repetitive/anxiety-like behaviour in Y maze and EPM tests, respectively, which were ameliorated by post-treatment with metformin in a dose-dependent manner. Moreover, prenatal VPA increased malondialdehyde (MDA) and nitrite levels as well as deficits in antioxidant enzymes activities in the hippocampus and prefrontal cortex (PFC) which were attenuated by metformin administration. Similarly, VPA-induced increase in acetylcholinesterase activity in the hippocampus and PFC were attenuated by postnatal treatment with metformin. Findings from this study showed that postnatal administration of metformin prevented valproic acid-induced autistic-like behaviour. Hence, metformin could be a potential adjunct in the management of autism spectrum disorders., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Objectives The brain's cholinergic system occupies a central role in normal cognition and age-related cognitive decline, including Alzheimer's disease (AD). This study sought to investigate the role of antioxidant defense and cholinergic systems on rutin-induced antiamnesia in mice. Methods Rutin (1, 5, or 50 mg/kg, p.o.) or vehicle (10 ml/kg, p.o.) was administered for three consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p) was given, 5 min post-scopolamine injection, open field, Y-maze, or Morris water maze (MWM) (five days consecutive training sessions) tasks was carried out. The mice were sacrificed on day 7 to assays for biomarkers of oxidative stress and cholinergic system. Results Scopolamine significantly reduced spontaneous alternation behavior in Y-maze and prolonged escape latency in MWM tasks when compared to vehicle-treated control indicative of working memory and spatial learning deficits. However, the pretreatment of mice with rutin (1, 5, or 50 mg/kg) prevented scopolamine-induced working memory and spatial learning impairments without affecting spontaneous locomotor activity. Scopolamine-induced nitrosative/oxidative stress and increased acetylcholinesterase activity in the prefrontal cortex and hippocampus were significantly attenuated by the pretreatment of mice with rutin. Conclusions rutin restored cognitive function in scopolamine-induced amnesia through enhancement of antioxidant defense and cholinergic systems.

Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the pathological mechanisms of PD to translate them into therapy has remained a high research priority. In this review, we highlight evidence describing the involvement of microglial dysfunction in PD. Thereafter, we provide current knowledge suggesting that the substantia nigra pars compacta and putamen, compared to other brain regions, show a reduced microglial density, as well as altered morphological and functional properties in homeostatic conditions, while presenting dystrophic features associated with aging. Further, we describe that this defective microglial programing emerges as early as the second postnatal week, persists until adulthood and impacts negatively on their transcriptional pattern and provision of local trophic support. We emphasize the role of α-synuclein oligomers as a major dysfunctional signal underlining microglial-mediated phenotypic switch and adaptive response contributing to neurodegeneration. Moreover, we explore available avenues should microglia be considered as target for neuroprotective or restorative strategies including preventing the aggregation of α-synuclein protofibrils formation. However, we provide a note of caution regarding the success of microglial-targeted PD strategies, using minocycline as an example. In conclusion, we discuss putative neuroprotective agents that were unsuccessful in previous trials but could be reconsidered by focusing on the stage of microglial-dependent pathogenic events during PD in suitable cohorts of patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is an infection caused by a newly discovered coronavirus which was identified in Wuhan, China. The race is on globally to repurpose drugs for COVID-19 and develop a safe and effective vaccine against the disease. There is an urgent need to search for effective remedies against COVID-19 from the rich and extensive flora of Africa and the world. A literature search was conducted to obtain information on drugs with the potential for effectiveness in the treatment of COVID-19 based mostly on outcomes of preclinical studies and a few clinical investigations. This was considered important to this perspective as some of the identified mechanisms of action may be related to potential anti-COVID-19 actions of phytomedicines. The findings from the literature search were also used to establish the need for exploration of phytomedicines in the fight against COVID-19. This perspective identifies the need to preserve the rich tradition of herbal medicine in Africa, repositioning it by inculcating all aspects of discovery, development, and chemical evaluation of pharmaceuticals from medicinal plants for effective management of prevalent diseases. The identified mechanisms of action of current drugs under consideration for the treatment of COVID-19 include preventing fusion of SARS-CoV-2 with human cells; decrease acidity in endosomes, cell membrane-derived vesicles for transportation of the virus within the host cell and within which the virus can replicate; and blockade of the production of proinflammatory cytokines. Phytomedicines may possibly elicit either one or a combination of these effects. The case for the exploration of phytomedicines against COVID-19 is strengthened by the emergence of a number of conventional drugs from medicinal plants and the emergence of botanicals with proven efficacy for some medical conditions. Caution against indiscriminate use of medicinal plants in the guise of treating COVID-19 has been highlighted and the need for reliable preclinical and clinical studies., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Dementia of Alzheimer disease type (AD) and type 2 diabetes mellitus (T2D) are two most common diseases of aging which has reached epidemic proportions. Moreover, there is a shared mechanism of pathogenesis between metabolic disorders and AD. Hence, the need for discivery of effective prevention and treatment strategies. Diastereomeric mixture of calophyllic acid and isocalophyllic acid (ISO) has been shown to stimulate glucose uptake through GLUT4- translocation. In this study, an attempt was made to investigate the effect of ISO on scopolamine-induced memory deficit in mice. ISO (5, 25 or 50 mg/kg, p.o.) or vehicle (10 ml/kg, p.o.) was administered for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was given before the animals were subjected to Y-maze, open field, novel object recognition (NOR) or Morris water maze (MWM; 5 consecutive days) paradigms. The mice were sacrificed 45 min after MWM test on day 8. The hippocampus and prefrontal cortex were rapidly isolated on ice for assay of biochemical markers of oxidative stress and acetylcholinesterase activity. Scopolamine reduced the percentage alternation behaviour in the Y-maze and discrimination index in NOR tests with no significant change in escape latency time in MWM task suggestive of deficit in learning and memory. However, the pretreatment of mice with ISO produced a dose-dependent improvement in learning and memory. Moreover, ISO administration attenuated scopolamine-induced increase in malondialdehyde/nitrite generation and acetylcholinesterase activity and deficit in antioxidant enzyme activity in the hippocampus and prefrontal cortex. Findings from this study showed that the diastereomeric mixture of calophyllic acid and isocalophyllic acid possesses anti-amnesic effect through enhancement of antioxidant defense and cholinergic signaling pathway.

ETHNOPHARMACOLOGY RELEVANCE: the root decoction of Cnestis ferruginea Vahl ex DC (Connaraceae) is widely used in traditional African medicine for the treatment of various ailments including pain, inflammation and epilepsy. We have earlier reported anticonvulsant effect of Cnestis ferruginea root extract in mice., Aim of the Study: to evaluate the effect of ethanolic root extract of Cnestis ferruginea (CF) on kainic acid (KA)-induced temporal lobe epilepsy (TLE) in mice as well as the involvement of inflammatory mediators and oxidative stress., Materials and Methods: mice were randomly divided into preventive treatment (vehicle (normal saline) or CF (400 mg/kg, p.o.) for 3 consecutive days before KA (5 mg/kg, i.p.) on days 4 and 5. In the reversal model, KA (5 mg/kg, i.p.) was administered on days 1 and 2 before vehicle or CF (400 mg/kg) administration on days 3-5. The effect of treatments on seizure severity was recorded using Racine scale. Animals were euthanized on day 5, 6 h after last KA exposure in preventive model and 1 h after CF administration in reversal model to estimate markers of oxidative stress and neuroinflammation., Results: exposure of mice to KA induced TLE evidenced in increased severity of seizures which was significantly reduced by the pre- and post-treatment of mice with CF. Moreso, KA-induced malondialdehyde/nitrite generation and GSH deficit in the brain were attenuated by CF treatments. KA-induced up-regulation of inflammatory transcription factors; cyclooxygenase-2 (COX-2) and nuclear facor-kappaB (NF-κB) in the CA1, CA2, CA3 and dentate gyrus (DG) regions of the hippocampus regions were attenuated by CF treatments., Conclusion: findings from this study showed that Cnestis ferruginea root extract ameliorated KA-induced TLE through enhancement of antioxidant defense mechanism and attenuation of neuro-inflammatory transcription factors. Thus, could possibly be a potential phytotherapeutic agent in the management of temporal lobe epilepsy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer disease (AD) is an age related neurodegenerative disease causing severe cognitive and memory decline in elderly people. Flavonoids play neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) or tau peptide into oligomers and fibrils. This study sought to investigate the effect of hesperetin (HPT) on scopolamine-induced memory impairments in mice. Mice were orally pretreated with HPT (1, 5 or 50 mg/kg) or vehicle (normal saline; 10 ml/kg) for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was administered 5 min before locomotor activity (open field test) and memory function (novel object recognition test (NORT) for 2 consecutive days and Morris water maze task (MWM) for 5 consecutive days). Levels of oxidative stress markers / brain derived neurotrophic factors (BDNF) and acetylcholinesterase activity were determined in the hippocampus and prefrontal cortex after completion of MWM task. Scopolamine caused no significant change in mice exploration of the familiar or novel object in the test session whereas the HPT-treated mice spent more time exploring the novel object more than familiar object in NORT. Scopolamine also increased the escape latency in acquisition phase and decreases time spent in target quadrant in probe phase which were ameliorated by the pretreatment with HPT. Scopolamine-induced alteration of oxidant-antioxidant balance, acetylcholinesterase activity and neurogenesis in the hippocampus and prefrontal cortex were attenuated by HPT treatment. This study showed that HPT ameliorated non-spatial/spatial learning and memory impairment by scopolamine possibly through enhancement of antioxidant defense, cholinergic and BDNF signaling.

Ethnopharmacological Relevance: Trianthema portulacastrum L. (Aizoaceae) is used in traditional African Medicine for the treatment of various illnesses including dropsy, inflammation and rheumatism., Aim of the Study: This study was designed to investigate the anti-nociceptive and anti-arthritic properties of the aqueous whole plant extract of Trianthema portulacastrum (AETP), possible mechanisms of action and characterize some of the active constituents., Materials and Methods: Antinociceptive activity was evaluated using the acetic acid-induced writhing and hot plate tests in mice. The carrageenan test was used to induce a transient inflammation while arthritis was induced with complete Freund's adjuvant (CFA) in rats. On completion of CFA-induced arthritis macroscopic observations, the rats were euthanized to isolate the spleen, liver and limbs for estimation of oxidative stress and histological analysis., Results: AETP (10, 50, or 250 mg/kg; p.o.) produced significant (p < 0.05) and dose-dependent inhibition (41.10, 50.40, and 67.10%, respectively) of writhing response elicited by acetic acid. Also, increased pain threshold of supraspinally mediated nociceptive behaviour, with peak maximum possible effect (MPE) obtained at 250 mg/kg (22.98%; 30 min post-treatment). However, the pre-treatment of mice with Nitro-L-arginine (L-NNA) or naloxone reversed AETP-induced antinociception. In another experiment, AETP produced time course inhibition of carrageenan-induced paw oedema with peak effect (50.60%) at 250 mg/kg as well as significant reduction in CFA-induced arthritis by 58.56%, on day 27 and arthritic index (26.84%). Similarly, AETP attenuated CFA-induced MDA generation and deficit in antioxidant enzyme activities. Histological analysis of rat joints revealed a reduction in the synovial hyperplasia and mononuclear infiltration induced by CFA in AETP treated groups., Conclusion: Findings from this study showed that T. portulacastrum possesses anti-nociceptive action through nitrergic and opioidergic signalling as well as anti-arthritic effect through enhancement of antioxidant defense system and inhibition of release or actions of inflammatory mediators., (Copyright © 2019. Published by Elsevier B.V.)

There is a growing number of epidemiological and molecular studies which suggest that diabetes is associated with an increased risk of Parkinson's disease (PD). Hence, in this study, the effect of glimepiride (GPD), a sulphonylurea (antidiabetic) on paraquat (PQT)-induced Parkinsonism was evaluated in mice. Thirty-six mice were randomly divided into six groups (n = 6) and treated orally for 21 consecutive days as follows: Group 1: vehicle (10 mL/kg), Group 2: PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 3-5: GPD (1, 2 or 4 mg/kg) + PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 6: GPD (4 mg/kg, p.o.). The effects of the treatment on motor coordination were evaluated using the rotarod performance, bar and open field tests while working memory was assayed using Y-maze test. Paraquat injection induced significant decrease in falling time, number of crosses and percentage alternation behaviour with a concomitant increase in the duration of cataleptic behaviour in the rotarod, open field, Y-maze and bar tests, respectively, which was ameliorated by GPD treatment. PQT also increased lipid peroxidation, peroxynitrite and TNF-α generations as well as deficit in superoxide dismutase and GSH activities in the midbrain. PQT-induced oxidative stress and neuroinflammation was attenuated by GPD treatment. Findings from this study showed that GPD prevents PQT-induced motor dysfunction, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of pro-inflammatory cytokine release. Thus, GPD could be a potential adjunct in the management of Parkinsonism., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Isorhamnetin (IRN), a 3'-O-methylated metabolite of quercetin has antioxidant, anti-inflammatory and neuroprotective properties. In this study, we investigated the learning and memory enhancing effects of IRN on spatial and non-spatial learning and memory deficits induced by scopolamine (3 mg/kg, i.p; muscarinic antagonist) using the novel object recognition test (NORT) and Morris water maze (MWM) task. IRN (1, 5 or 50 mg/kg, p.o.) or vehicle was administered to male albino for 3 consecutive days, scopolamine was given 1 h after last administration on day 3. Five minutes post scopolamine administration the behavioural test of cognitive function was carried out. One hour after probe test (MWM task) on day 7, the brains were isolated to assay for oxidative stress, cholinesterase activity and brain derived neurotrophic factor (BDNF) levels in the prefrontal cortex (PFC) and hippocampus (HIPPO). IRN treatment significantly improved scopolamine-induced learning and memory impairment in behavioural tests. IRN reduced malondialdehyde and nitrite generation induced by scopolamine through increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities in the prefrontal cortex and hippocampus. In addition, IRN attenuates scopolamine induced cholinesterase activity and BDNF level in the prefrontal cortex and hippocampus of mice. Findings from this study showed that IRN possesses cognition and memory enhancing properties possibly through enhancement of antioxidant defense system, cholinergic signaling and synaptic plasticity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background Tetracera alnifolia Willd. (Dilleniaceae) is used in traditional African Medicine for the treatment of headache, abdominal pain, and rheumatism. Hence, this study sought to investigate the antinociceptive and anti-inflammatory effects of the hydroethanolic leaf extract of T. alnifolia (HeTA) in rodents. Methods Antinociceptive activity was evaluated using the acetic acid-induced writhing, formalin-/capsaicin-induced paw licking and hot plate tests in mice. The contribution of opioidergic, l-arginine-nitric oxide, and ATP-sensitive potassium channel pathways in HeTA-induced antinociception was also evaluated. The anti-inflammatory effect was assessed using the carrageenan-induced paw edema, xylene ear edema, cotton pellet granuloma, and complete Freund's adjuvant (CFA)-induced arthritis in rats. Results HeTA (100, 200, and 400 mg/kg, p.o.) produced significant (p<0.05) decrease in mean number of acetic acid-induced writhing, time spent licking paw in formalin, and capsaicin tests as well as time course increase in nociceptive reaction latency in hot plate test. HeTA-induced antinociception was prevented by pretreatment of mice with naloxone (non-selective opioid receptor antagonist), l-arginine (nitric oxide precursor), or glibenclamide (ATP-sensitive potassium channel blocker). HeTA (100 mg/kg, p.o.) produced a significant anti-inflammatory effect against carrageenan-induced rat paw edema (1-5 h), xylene-induced ear edema, cotton pellet-induced granuloma formation, and CFA-induced arthritis in rats. The effects of HeTA in various models were similar to the effect of the standard reference drugs. Conclusions Findings from this study showed that HeTA possesses antinociceptive effect possibly mediated through peripheral opioid receptors with activation of l-arginine-nitric oxide and ATP-sensitive potassium channel pathway as well as anti-inflammatory activity.

Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease caused by age, genetic and environmental factors such as paraquat (PQT). PQT (a quartenary nitrogen herbicide) is implicated in some form of idiopathic PD. This study sought to investigate the protective effect of vinpocetine on paraquat-induced Parkinsonism in mice. Forty-eight male albino mice were randomly divided into 6 groups and treated orally as follows for 21 days; Group 1: vehicle normal (10 ml/kg), group 2: vehicle control (10 ml/kg); groups 3-5: vinpocetine (5, 10 or 20 mg/kg); group 6: vinpocetine (20 mg/kg). Animals in groups 2-5 were given PQT (10 mg/kg, i.p.) every 3 days for 3 weeks. The effect of treatments on spontaneous motor activity (open field test), muscle coordination (rotarod tests), cataleptic behaviour (bar test), and working memory (Y-maze test) were assayed. After the behavioural assay on day 21, the midbrain was isolated for estimation of oxidative stress and TNF-α. Intraperitoneal injection of paraquat significantly induced motor deficits, muscle incoordination, catalepsy and working memory impairment which was ameliorated by the pretreatment of mice with vinpocetine. In addition, paraquat injection caused marked increase in nitroso-oxidative stress markers with concomitant deficits in antioxidant enzymes activities (GSH and SOD) as well as induction of tumour necrotic factor-α (TNF-α) in the mid-brain which were attenuated by the pretreatment of mice with vinpocetine. Findings from this study showed that vinpocetine prevented paraquat-induced motor deficits, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of neuroinflammatory cytokine. Thus, could be a potential drug in the management of Parkinsonism.

Objective: This study sought to evaluate the protective effect of ethanolic leaf extract of Moringa oleifera on testosterone-induced benign prostatic hyperplasia (BPH) in male Sprague-Dawley rats., Materials and Methods: BPH was induced in rats by the administration of testosterone propionate (3 mg/kg, s.c., in olive oil) for 4 weeks. M. oleifera (50, 100, or 200 mg/kg), celecoxib (20 mg/kg), or M. oleifera (50 mg/kg) + celecoxib (20 mg/kg) were orally administered daily 15 min before testosterone. On day 29, blood was collected to measure the levels of serum testosterone and prostate-specific antigen before the animals were sacrificed. The prostates were weighed, assayed, and histologically examined., Results: M. oleifera significantly reduced the testosterone-induced increase in prostate weight (20.16%), prostate index (65.85%), serum testosterone (72.86%), and prostate-specific antigen (48.49%). Testosterone caused a significant increase in malondialdehyde (73%) as well as a reduction in glutathione (62.5%), superoxide dismutase (50%), and catalase (64%) activities which were attenuated by M. oleifera with a peak effect obtained at 100 mg/kg. The disruption of prostate histoarchitecture by testosterone was also ameliorated by M. oleifera., Conclusion: M. oleifera prevented testosterone-induced BPH through enhancement of antioxidant defence mechanisms, and hence could be used as an adjunct in the treatment of BPH., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background Cisplatin-induced acute liver and kidney injuries are serious problems in cancer patients during treatment of solid tumours. Objective This study sought to investigate possible protective effect of ethanolic fruit extract of Citrullus colocynthis (CC) against cisplatin-induced hepato-renal toxicity in rats. Methods Thirty male albino rats (150-200 g) were divided into five groups (n=6) and treated as follows: group 1: vehicle (10 mL/kg, p.o.; normal control); group 2: vehicle (10 mL/kg); groups 3-5: CC (100, 200 or 400 mg/kg, p.o.), respectively, for 10 days. Cisplatin (7.5 mg/kg; i.p.) was administered on the 7th day to animals in groups (2-5) 1 h after pretreatment. The animals were euthanized on day 10 for haematological, biochemical and histological analysis. Results Cisplatin induced a significant increase in the serum levels of ALT, ALP, creatinine and blood urea nitrogen indicative of hepato-renal injury. More so, cisplatin caused marked increase in granulocyte, lymphocyte and platelets counts which were ameliorated by CC (100-400 mg/kg) treatment. In addition, cisplatin induced marked increase in MDA and nitrite levels coupled with deficits in glutathione, catalase and superoxide dismutase activities which were attenuated by CC administration. In vitro assay showed that CC scavenged DPPH and nitrite radicals (69.50 and 64.50 µg/mL, respectively). Total antioxidant capacity, phenolic and flavonoid contents are 24.27±0.09 mg QUE/g, 17.14±0.12 mg GAE/g and 10.20±0.09 mg QUE/g, respectively. CC preserved the liver and kidney histoarchitecture. Conclusions This study showed that C. colocynthis possesses hepatoprotective and nephroprotective actions possibly through enhancement of antioxidant defence system. Thus, it could be a potential adjuvant in cisplatin-based chemotherapy.

Benign prostatic hyperplasia (BPH) is a common health problem in ageing men. This study was carried out to investigate the protective effect of telmisartan on testosterone-induced BPH in rats. Fifty-four male Wistar rats (200-250 g) were randomly divided into nine groups (n = 6) and orally treated for 28 consecutive days: group 1 - vehicle normal, olive oil (10 mL/kg); group 2 - BPH model control (10 mL/kg); groups 3-5 - telmisartan (5, 10 or 20 mg/kg, respectively); group 6 - pioglitazone (20 mg/kg); group 7 - celecoxib (20 mg/kg); group 8 - combination of telmisartan (5 mg/kg) and pioglitazone (20 mg/kg); group 9 - combination of telmisartan (5 mg/kg) and celecoxib (20 mg/kg). Animals in groups 2-9 were given testosterone propionate in olive oil (3 mg/kg) subcutaneously 15 min after pretreatments. On day 29, blood was collected for the estimation of serum testosterone and prostate-specific antigen (PSA). The prostates were excised, weighed and subjected to biochemical and histological studies. Testosterone injection induced significant increase in prostatic index, serum testosterone and PSA suggesting BPH as well as increased prostate oxidative stress which were ameliorated with the pretreatment of rats with telmisartan or co-administration of celecoxib and pioglitazone. Histological examination showed that testosterone disrupted the morphology of the prostate epithelial cells evidenced in the involution of the epithelial lining of the acini into the lumen indicating BPH which was reversed by telmisartan. Findings from this study showed that telmisartan alone or in combination with pioglitazone prevented the development of testosterone-induced prostatic hyperplasia., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Diabetes and obesity have been reported to alter sex steroid hormone metabolism. In this study, an attempt was made to investigate the protective effect of atorvastatin (ATR) in combination with celecoxib (CEL) or pioglitazone (PIO) on testosterone-induced BPH in rats. Male Wistar rats (200-250 g) were randomly divided into nine groups (n = 8) and orally treated as follows for 28 consecutive days: group 1: vehicle control (10 mL/kg); group 2: vehicle testosterone (10 mL/kg); groups 3 - 5: ATR (0.5, 2.5, and 5 mg/kg, respectively); group 6: CEL (20 mg/kg); group 7: PIO (20 mg/kg); and groups 8-9: ATR 0.5 mg/kg, and 15 min later, animals were given CEL (20 mg/kg) or PIO (20 mg/kg), respectively. One hour post-treatment, animals in groups 2-9 were given testosterone propionate (3 mg/kg, s.c.). Twenty-four hours after last treatment on day 28, blood was collected for serum testosterone and prostate-specific antigen (PSA) analysis. Prostate was harvested for biochemical and histological assays. Subcutaneous injection of testosterone increased serum levels of testosterone and PSA which was ameliorated by pretreatments of rat with ATR, celecoxib, or pioglitazone. Similarly, testosterone-induced increase in MDA and reduction in the activity of GSH, superoxide dismutase (SOD), and catalase were attenuated by ATR. Conversely, celecoxib or pioglitazone treatment failed to affect the activity of antioxidant enzymes. The histology of the prostate showed significant improvement in prostatic cells of ATR, celecoxib, or pioglitazone treated. Findings from the study showed that atorvastatin attenuated testosterone-induced BPH. Moreover, synergistic effect was observed when atorvastatin was combined with celecoxib., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Gymnosporia heterophylla (Celastraceae) is an African medicinal plants used to treat painful and inflammatory diseases with partial scientific validation. Solvent extractions followed by repeated chromatographic purification of the G. heterophylla aerial parts led to the isolation of one new β-dihydroagarofuran sesquiterpene alkaloid (1), and two triterpenes (2-3). In addition, eight known compounds including one β-dihydroagarofuran sesquiterpene alkaloid (4), and six triterpenes (5-10) were isolated. All structures were determined through extensive analysis of the NMR an MS data as well as by comparison with literature data. These compounds were evaluated for the anti-inflammatory activities against COX-1 and -2 inhibitory potentials. Most of the compound isolated showed non selective COX inhibitions except for 3-Acetoxy-1β-hydroxyLupe-20(29)-ene (5), Lup-20(29)-ene-1β,3β-diol (6) which showed COX-2 selective inhibition at 0.54 (1.85), and 0.45 (2.22) IC 50 , in mM (Selective Index), respectively. The results confirmed the presence of anti-inflammatory compounds in G. heterophylla which are important indicators for development of complementary medicine for inflammatory reactions; however, few could be useful as selective COX-2 inhibitor., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In Alzheimer's disease (AD) basal forebrain cholinergic neurons appear to be targeted primarily in early stages of the disease. Scopolamine (muscarinic receptor antagonist) has been used for decades to induce working and reference memory impairment in rodents. In this study, we evaluated the protective effect of kolaviron, a biflavonoid complex isolated from Garcinia kola seeds extract against scopolamine-induced memory impairment/oxidative stress. Rats were pretreated with kolaviron (25, 50 or 100 mg/kg p.o.) for 3 consecutive days, scopolamine (3 mg/kg, i.p.) was administered 1 h post-treatment on day 3. Five minutes post-scopolamine injection, memory function was assessed using the Y-maze or Morris water maze tests (MWM) in rats. The rats were sacrificed and brains isolated on the 8th day after the MWM test for estimation of acetylcholinesterase activity and nitrosative/oxidative stress status. Scopolamine injection induced deficit (P < 0.05) in percentage alternation behaviour in the Y-maze test indicating memory impairment which was ameliorated by kolaviron in a dose-dependent manner. Also, pre-training treatment with kolaviron significantly improved spatial learning evidenced in the session-dependent and more efficient localization of the hidden platform in the MWM test. Moreover, scopolamine injection induced significant increase in lipid peroxidation (prefrontal cortex), nitrite generation (striatum and hippocampus) and a decrease in glutathione (prefrontal cortex, striatum and hippocampus) and superoxide dismutase (striatum and hippocampus) level which was attenuated by kolaviron pre-treatment. These findings showed that kolaviron possesses cognition enhancing effect through enhancement of antioxidant defense and cholinergic systems.

We have earlier reported antidepressant-like effect of Cnestis ferruginea and its bioflavonoid constituent, amentoflavone in behavioural paradigms but its effects on neurochemical and neuroendocrine systems are yet to be elucidated. This study sought to investigate the effect of subchronic treatment of C. ferruginea (CF) on monoamines system, hypothalamo-pituitary adrenal axis and nitrosative/oxidative stresses. Male albino rats (150-200g) randomly divided into seven groups; Group I: vehicle treated (0.2% v / v Tween 80 in normal saline (10ml/kg; p.o.; unstressed), Group II: vehicle treated+restraint stress, Group III: imipramine (20mg/kg; p.o.), Group IV-VI: CF (12.5, 50, or 100mg/kg; p.o., respectively), Group VII: CF 6.25+imipramine 5mg/kg. One hour post-treatment, animals were subjected to 20min restraint stress and 6min, forced swim test (FST) for a period of 14 days. CF (12.5, 50 and 100mg/kg) produced significant reduction in immobility time and an increase in climbing behaviour. CF attenuated repeated restraint stress×FST-induced serum corticosterone [F(6,28)=5.45,P<0.01]. Exposure of rats to FST+restraint stress paradigms produced significant (P<0.05) increase in malondialdehyde and nitrite level, also reduced the glutathione level and superoxide dismutase activity which was reversed by subchronic treatment of rats with CF. Restraint stress×FST significantly decreased NA, DA and 5-HT concentrations, with increased DA and 5-HT turnover ratios in discrete brain regions which was ameliorated by CF or imipramine subchronic treatment. These results suggest that the antidepressant-like effect of C. ferruginea involved enhancement of monoamines and antioxidant as well as normalization of neuroendocrine systems., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Grains of paradise ( Aframomum melegueta ) K. Schum is used to flavour foods and used as memory enhancer and anti-aging in traditional African medicine. This study examine the influence of ethanolic seed extract of Aframomum melegueta (AFM) on cognitive impairment induced by scopolamine in rodents. Methods: AFM (6.25, 12.5 or 25 mg/kg, p.o .) or tacrine (5 mg/kg, i.p .) was administered for 3 consecutive days, 1 h post-treatment on day 3, scopolamine (3 mg/kg, i.p .) was given, 5 min later, cognition was evaluated in the Y-maze and elevated plus maze (EPM) tests in mice as well as the Morris water maze (MWM) paradigm in rats. Biomarkers of oxidative stress in the prefrontal cortex, striatum and hippocampus of rats were evaluated after the MWM task. The antioxidant capacity of AFM was evaluated in vitro using the 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric ion reducing power (FRAP) assays. Results: Scopolamine significantly reduced (38.72%) spontaneous alternation behavior in the Y-maze and increase in transfer latency in the EPM test on day 2, which was ameliorated by AFM (25 mg/kg; 49.86%, 71.55%, respectively) in mice. In addition, AFM prevented the spatial learning deficit induced by scopolamine in the MWM task. Similarly, scopolamine-induced oxidative-nitrosative stress was attenuated by AFM treatment, evidenced in decreased malondialdehyde and nitrite levels, restoration of glutathione and superoxide dismutase levels. Interestingly, AFM exhibited notable scavenging activities against DPPH, NO and FRAP radicals. Conclusion: These results showed that A. melegueta seed extract prevented scopolamine-induced memory impairments through enhancement of antioxidant defense systems., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Mangifera indica (Anacardiaceae) is an important herb in the traditional African and Ayurvedic medicines. The stem barks are used in the treatment of hypertension, insomnia, tumour, depression, rheumatism and as a tonic. This study was carried out to investigate antidepressant- and anxiolytic-like effect of the hydroethanol stem bark extract of M. indica (HeMI) in mice., Methods: HeMI (12.5-100 mg/kg, p.o.) was administered 1 h before subjecting the animal to the forced swim test (FST), tail suspension test (TST) and elevated plus maze tests (EPM)., Results: HeMI (12.5-100 mg/kg, p.o.) treatment produced significant reduction in immobility time [F(6.56)=8.35, p<0.001], [F(6,56)=7.55, p<0.001] in the FST and TST, respectively. Moreover, co-administration of sub-therapeutic doses of imipramine or fluoxetine with HeMI (3.125 mg/kg) elicited significant reduction in time spent immobile in the FST. However, pretreatment of mice with parachlorophenylalanine, metergoline, yohimbine or sulpiride abolished the antidepressant-like effect elicited by HeMI. In the EPM, HeMI produced significant [F(5,42)=8.91, p<0.001] increase in open arms exploration by 75.55 % and this effect was blocked by pretreatment of mice with flumazenil or metergoline., Conclusions: Findings from this study showed antidepressant-like effect of M. indica through interaction with 5-HT2 receptor, α2-adrenoceptor and dopamine D2-receptors. Also, an anxiolytic-like effect through its affinity for 5-HT2 and benzodiazepine receptors. Hence, M. indica could be a potential phytotherapeutic agent in the treatment of mixed anxiety-depressive illness.

Metformin, a well-known antidiabetic drug, has recently been proposed to promote neurogenesis and to have a neuroprotective effect on the neurodegenerative processes induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in models of Parkinson's disease. Interestingly, metformin has antioxidant properties and is involved in regulating the production of cytokines released during the neuroinflammatory process. Several studies have reported that 3,4-methylenedioxymethamphetamine (MDMA), a recreational drug mostly consumed by young adults, produces a persistent loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and caudate putamen (CPu) of mice. The aim of this study was to investigate the potential neuroprotective effect of metformin against short- and long-term neurotoxicity induced by MDMA and its role on MDMA-induced hyperthermia. Adult mice received metformin (2 × 200 mg/kg, 11-h intervals, administered orally), MDMA (4 × 20 mg/kg, 2-h interval, administered intraperitoneally), or MDMA plus metformin (2 × 200 mg/kg, 1 h before the first MDMA administration and 4 h after the last). On the second and third day, mice were treated with vehicle or metformin (1 × 200 mg/kg) and sacrificed 48 h and 7 days after the last MDMA administration. The neuroprotective effect of metformin on MDMA-induced dopaminergic damage was evaluated by dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunohistochemistry in SNc and CPu. Metformin prevented the MDMA-induced loss of TH-positive neurons in the SNc and TH- and DAT-positive fibers in CPu, both at 48 h and 7 days after the last MDMA administration. These results show that metformin is neuroprotective against the short- and long-lasting dopaminergic neurodegeneration induced by MDMA.

Background: We have previously reported antidepressant effect of Cnestis ferruginea (CF) in behavioral models of depression. Due to the promise shown by this extract, this study was carried out to investigate the contribution of monoaminergic, cholinergic and nitrergic systems to the antidepressant-like effect elicited by CF., Methods: Male albino mice were pretreated with monoaminergic or cholinergic receptor antagonists, L-arginine or N(G)-nitro-L-arginine (nitric oxide synthase inhibitor) (at doses reported to block the in vivo effect of the agonists), 15 min before oral administration of CF (100 mg/kg), 1 h later, the forced swim test (FST) in mice was carried out., Results: CF treatment produced significant changes in the duration of swimming (F(5,42)=9.86, P<0.001), climbing behaviour (F(5,42)=4.51, P=0.004) and mean time spent immobile (F(5,42)=11.55, P<0.001) vs. vehicle-treated control. Co-administration of CF with fluoxetine or imipramine potentiated their effect. However, pretreatment of mice with reserpine (F(1,16)=119.20, P<0.001), prazosin (F(1,16)=68.98, P<0.001), sulpiride (F(1,16)=15.46, P<0.01), RS 127445 ((F(1,20)=8.22, P<0.01), SB 399885 ((F(1,20)=38.44, P<0.001), atropine (F(1,16)=53.77, P<0.001), or L-arginine (nitric oxide precursor) (F(1,16)=10.35, P<0.01) prevented CF-induced antidepressant-like effect in mice. In addition, pretreatment of mice with L-NNA (10 mg/kg) augmented the effect of CF., Conclusion: C. ferruginea exerts its antidepressant-like action through interaction with α-adrenoceptor, dopamine D2, 5-HT2B, 5-HT6 and muscarinic cholinergi1c receptors as well as L-arginine-nitric oxide systems. C. ferruginea could be used as adjuvant with conventional antidepressants in the treatment of major depressive disorder., (© Georg Thieme Verlag KG Stuttgart · New York.)