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Background and Aims To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable. Methods The study was performed in mitochondria isolated from liver of Wistar rats. Oxa (200 μg/mL) and CMN (5 μmol) were incubated under in vitro conditions. Results Oxa evoked a significant increase in the membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, decrease in reduced glutathione (GSH) and nonprotein thiol (NP-SH) levels. Oxa also caused a marked decline in the activities of enzymatic antioxidants and respiratory chain enzymes (I, II, III and V) in liver mitochondria. CMN pre-treatment significantly prevented the activities of enzymatic antioxidants and mitochondrial respiratory chain enzymes. CMN also restored the LPO and PC contents, GSH and NP-SH levels in liver mitochondria. Conclusion CMN intake might be effective in regulation of Oxa-evoked mitotoxicity during chemotherapy. Moreover, it is included in the armamentarium for anticancer agent-induced oxidative stress. [ABSTRACT FROM AUTHOR]

[Display omitted] Traumatic brain injury (TBI) triggers a bevy of changes including mitochondrial dysfunction, apoptosis, oxidative stress, neurobehavioural impairment, and neuroinflammation, among others. Dantrolene (DNT), a muscle relaxant which inhibits intracellular Ca2+ signaling from the ER, has been repurposed as a potential neuroprotective agent in various neurological diseases. However, there have been limited studies on whether it can mitigate TBI-induced deficits and restore impaired mitochondrial dynamics. This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary Acidic Protein (GFAP) and immunohistochemistry with NF-κβ to investigate neuroinflammation. H&E staining was also performed post-TBI. Our findings revealed DNT administration inhibits mitochondria-mediated apoptotis and reduces heightened oxidative stress. DNT treatment was also found to reverse neurobehavioural impairments and offer neuroprotection by preserving neuronal architechture. We also demonstrated that DNT inhibits neuronal autophagy and alleviates neuroinflammation following TBI by modulating the NF-κβ/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection. [ABSTRACT FROM AUTHOR]

There is increasing recognition of the magnitude of mitochondria in neurodegenerative disorders. Mitochondria play a key role in apoptotic and necrotic cell death. Melatonin (Mel), an indoleamine produced in several organs including the pineal gland has been known for its neuroprotective actions. In our study, we have investigated whether the mitochondrial ATP sensitive potassium (mtK ATP ) channel blocker 5-hydroxydecanoate (5-HD) and calcium (Ca 2 + ) affects permeability transition pore (PTP) alterations in isolated brain mitochondria treated with melatonin (Mel) and cyclosporin A (CsA). Mitochondrial swelling, mitochondrial membrane potential (Δψ m ), ROS measurement and mitochondrial respiration were evaluated in isolated brain mitochondria. In our results, mitochondrial swelling stimulated by exposing Ca 2 + ions and 5-HD associated by mPTP opening as depicted by modulation of CsA and Mel. In addition, Ca 2 + and 5-HD decreased Δψ m , depleted intracellular ROS, and inhibition of mitochondrial respiration (state 3 and state 4) in isolated brain mitochondria. Addition of Mel and CsA has shown significant restoration in mitochondrial swelling, Δψ m , intracellular ROS measurement and mitochondrial respiration in isolated brain mitochondria. Therefore, we speculate the modulatory effect of Mel and CsA in mitochondria treated with 5-HD and Ca 2 + hinders the mPTP-mediated mitochondrial dysfunction and cellular oxidative stress. We conclude that inhibition of mPT is one likely mechanism of CsA's and its neuroprotective actions. Development of neuroprotective agents including Mel targeting the mPTP therefore bears hope for future treatment of severe neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Neurotoxicity is a burdensome consequence of platinum-based chemotherapy that neutralizes the administration of effective dosage and often prompts treatment withdrawal. Oxaliplatin (Oxa), a third-era platinum analogue that is active against both early-organize and progressed colorectal growth, produces critical neurotoxicity. It has been reported that the Melatonin (Mel) is a pineal hormone its metabolites display important antioxidant properties in nervous system. There is dearth of literature involving the role of mitochondria and cytosolic compartments mediated Oxa-induced neurotoxicity and its underlying mechanisms are still debatable. Rats were pre-treated with Mel (10 mg/kg b.wt., i.p. ) and treated with Oxa (4 mg/kg b.wt. i.p. ) for 5 consecutive days. For neurobehavioral performances, decreased locomotor activity and muscular strength were observed in rats. Treatment with Mel in Oxa treated rats could protect the Oxa induced alterations in motor activity and muscular strength. For painful neuropathy, thermal hyperalgesia/nociceptive tests were evaluated. In addition, pre-treatment of Mel could block or alter the inactivation of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c (Cyt c) release in an Oxa rich environment. Pre-treatment of Mel have shown an alteration in hyperalgesia behaviour in Oxa treated rats. Oxidative stress biomarkers, levels of non-enzymatic antioxidants and mitochondrial complexes were evaluated against neurotoxicity induced by Oxa. Mel pre-treatment replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. Mel also modulated altered non-enzymatic, enzymatic antioxidants and complex enzymes of mitochondria. Futures studies are also required to identify other molecular markers involved in neurotoxicity induced by Oxa and possible action of Mel in its modulation. [ABSTRACT FROM AUTHOR]

Background and Aims Oxaliplatin is a widely employed platinum-derived chemotherapeutic agent commonly used for the treatment of colorectal cancer. Unfortunately, the benefit of this important drug is compromised by severe side effects such as neuropathy, ototoxicity, gastrointestinal toxicity, and hematological toxicity. Recently, few studies have also suggested the occurrence of hepatotoxicity in oxaliplatin-treated patients. Mitochondria have emerged as targets for anticancer drugs in various kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. Oxidative stress is a well-established biomarker of mitochondrial toxicity. The purpose of this study was to investigate the dose-dependent damage caused by oxaliplatin on isolated liver mitochondria under in vitro conditions. Methods The study was conducted in mitochondria isolated from liver of Wistar rats. Oxaliplatin was incubated with mitochondria in a dose-dependent manner under in vitro conditions. Oxidative stress indexes, non-enzymatic and enzymatic antioxidants were evaluated, looking at the overall armamentarium against the toxicity induced by oxaliplatin. Results Oxaliplatin caused a significant rise in the mitochondrial oxidative stress indexes lipid peroxidation and protein carbonyl. Alterations in the levels of non-enzymatic antioxidants and activities of enzymatic antioxidants were also observed. Conclusion Oxidative stress plays an important role in the mitochondrial toxicity of oxaliplatin. The integrity of the hepatic tissue is compromised by the reactive oxygen species-mediated lipid peroxidation and protein carbonyl formation. [ABSTRACT FROM AUTHOR]

• Mitochondrial dysfunction has been recognized as a hallmark in ischemia/reperfusion neural damage. • Ropinirole is considered as a promising neurological and functional recovery agent. • Ropinirole restores neurological function and histopathological changes after ischemic injury. • Ropinirole treatment is beneficial in preserving the mitochondrial functions. Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies. [ABSTRACT FROM AUTHOR]

Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 μM) and Mel (100 μM) at 25 °C for 1 h was given prior to TNPs (50 μg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure. [ABSTRACT FROM AUTHOR]

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential. [Display omitted] [ABSTRACT FROM AUTHOR]

Ischemic reperfusion (I/R) injury causes a wide array of functional and structure alternations of mitochondria, associated with oxidative stress and increased the severity of injury. Despite the previous evidence for N -acetyl-L-cysteine (NAC) provide neuroprotection after I/R injury, it is unknown to evaluate the effect of NAC on altered mitochondrial autophagy forms an essential axis to impaired mitochondrial quality control in cerebral I/R injury. Male wistar rats subjected to I/R injury were used as transient Middle Cerebral Artery Occlusion (tMCAO) model. After I/R injury, the degree of cerebral tissue injury was detected by infarct volume, H&E staining and behavioral assessment. We also performed mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometry and mitochondrial respiratory complexes to evaluate the mitochondrial dysfunction. Finally, we performed the western blotting analysis to measure the apoptotic and autophagic marker. We found that NAC administration significantly ameliorates brain injury, improves neurobehavioral outcome, decreases neuroinflammation and mitochondrial mediated oxidative stress. We evaluated the neuroprotective effect of NAC against neuronal apoptosis by assessing its ability to sustained mitochondrial integrity and function. Further studies revealed that beneficial effects of NAC is through targeting the mitochondrial autophagy via regulating the GSK-3β/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway. Our results suggest that NAC exerts neuroprotective effects to inhibit the altered mitochondrial changes and cell death in I/R injury via regulation of p-GSK-3β mediated Drp-1 translocation to the mitochondria. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum , which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 β (IL-1β) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS. Schematic representation of mitochondria mediated mechanisms of neuroprotection against ischemic stroke provided by Piperine. Piperine can inhibit mitochondrial dysfunction by suppressing inflammation and mitochondrial ROS mediated alterations in ETC and reduced mitochondrial membrane permeability (Δѱm) thereby preserving mitochondrial Cyt c level through blockage of mitochondrial permeability transition pore (mPTP). Finally, it might increase anti-apoptotic (Bcl-2) protein and decrease pro-apoptotic (Bax) protein, and alleviated neuronal cell death. Piperine also involved in cell survival processes and ultimately rescued neuronal morphological alterations and neurobehavioral abnormalities. IL-1β (Interleukin-1β), GFAP (Glial Fibrillary Acidic Protein), LPO (Lipid Peroxidation), GSH (Glutathione), Cyt c (Cytochrome c), Electron transport chain (ETC), Reactive oxygen species (ROS). [Display omitted] • Ischemic animals pre-treated with piperine showed reduced neurological alterations and infarct volume. • Piperine improved mitochondrial dysfunction. • Piperine showed anti-apoptotic potential by preventing cytochrome c release from mitochondria to cytoplasm. • PIP reduced neurological impairment and enhanced cell survival. [ABSTRACT FROM AUTHOR]

Cerebral ischemic stroke leads to mitochondrial alterations which are key factors for initiation of various cascades resulting in neuronal damage. Dopamine D2 receptor (D2R) agonist, Sumanirole (SUM) has been reported to possess anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the role of SUM in ischemic stroke (IS) has not been studied yet. The aim of the present study was to investigate the neuroprotective efficiency of SUM against ischemic injury and its possible effect on mitochondrial restorative mechanisms. Transient middle cerebral artery occlusion (tMCAO) was performed in Wistar rats for 90 min occlusion and 22.5 h reperfusion to mimic ischemic stroke. Post- treatment with Sumanirole (0.1 mg/kg and 1 mg/kg; s.c.) was done at 1 h, 6 h, 12 hand 18 h after surgery. In addition, neurobehavioral analysis, mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometric analysis, mitochondrial complexes analysis, infarct size evaluation and histological analysis were performed. Sumanirole restored behavioural alterations as measured by rotarod performance, grip strength, adhesive tape removal analysis and neurological deficits. In addition, it also refurbished mitochondrial dysfunction by decreasing mitochondrial reactive oxygen species production, elevating mitochondrial membrane potential and by protecting the activity of mitochondrial complexes along with histological alterations. As a result, infarct sizes were markedly reduced in tMCAO surgery animals. Findings from the study provide evidence that SUM promotes neuronal survival in in vivo model of IS through mitochondria mediated neuroprotective features. • We investigated the neuroprotective efficiency of highly selective dopamine D2 agonist Sumanirole against ischemic injury. • Sumanirole restored behavioural alterations and neurological deficits in a stroke rodent mode. • Mitochondrial dysfunction was attemnuated by decreasing mitochondrial ROS production. • Infarct sizes were markedly reduced in tMCAO surgery animals. • Our study provides evidence for mitochondrial mediated neuroprotective features of Sumanirole against ischemic stroke. [ABSTRACT FROM AUTHOR]