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Perinatal asphyxia (PA)-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and long-term sequelae such as spastic motor deficits, intellectual disability, seizure disorders and learning disabilities. The brain injury is secondary to both the hypoxic-ischemic event and oxygenation-reperfusion following resuscitation. Following PA, a time-dependent progression of neuronal insult takes place in terms of transition of cell death from necrosis to apoptosis. This transition is the result of time-dependent progression of pathomechanisms which involve excitotoxicity, oxidative stress, and ultimately mitochondrial dysfunction in developing brain. More precisely mitochondrial respiration is suppressed and calcium signalling is dysregulated. Consequently, Bax-dependent mitochondrial permeabilization occurs leading to release of cytochrome c and activation of caspases leading to transition of cell death in developing brain. The therapeutic window lies within this transition process. At present, therapeutic hypothermia (TH) is the only clinical treatment available for treating moderate as well as severe asphyxia in new-born as it attenuates secondary loss of high-energy phosphates (ATP) (Solevåg et al. in Free Radic Biol Med 142:113-122, 2019; Gunn et al. in Pediatr Res 81:202-209, 2017), improving both short- and long-term outcomes. Mitoprotective therapies can offer a new avenue of intervention alone or in combination with therapeutic hypothermia for babies with birth asphyxia. This review will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after PA, as a means of identifying new avenues of therapeutic intervention., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Current pharmacotherapy for post-traumatic stress disorder (PTSD) is limited to few antidepressants. Mitochondrial dysfunction is observed in PTSD, along with altered potassium homeostasis. Nutritional supplementation of taurine can improve ionic homeostasis and thereby treat PTSD-like symptoms in rats., Aim: The purpose is to study the pharmacological effect of taurine in stress re-stress-induced PTSD in rats., Methods: As per protocol, animals were restrained for 2 h then exposed to footshock (FS) (2 mA/10 s) followed by halothane-induced anesthesia. Behavioral assessments such as elevated plus maze (EPM) and Y-maze tests were performed on days 2, 8, and 32 of experimental protocol after re-stress. In addition, daily oral administration of taurine (100, 200, and 300 mg/kg) and paroxetine (PAX) (10 mg/kg) was done from D-8 to D-32 followed by re-stress. The plasma concentration of taurine, corticosterone, and potassium was measured on Day-32 along with mitochondrial function in discrete brain regions., Results: Sub-chronic administration of taurine in high and medium doses significantly ameliorated PTSD-like symptoms such as hyperarousal, anxiety, and improved spatial recognition memory. Taurine in all doses restored the plasma concentration of corticosterone and potassium. SRS-induced alterations in mitochondrial bioenergetics, complex enzyme activities, and reduced mitochondrial membrane potential in different brain regions were ameliorated by taurine., Conclusion: Nutritional supplementation of taurine improves potassium ionic homeostasis, mitochondrial function, and attenuated PTSD-like symptoms in SRS subjected rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is one of the widely reported neurodegenerative disorders affecting more than ten million people worldwide. Due to therapeutic limitations and several adverse effects associated with currently used drugs, it is crucial to search for safe and effective options for treatment of PD. Oxidative stress, mitochondrial dysfunction, α-synuclein oligomeric aggregates, and glucocerebrosidase (GCase) deficiency are involved in PD pathogenesis. Rebamipide, an anti-ulcer drug, is a proven free-radical scavenger and antioxidant. The drug has shown neuroprotective effects in cultured SH-SY5Y cells. Therefore, we investigated the pharmacological effect of rebamipide in 6-hydroxydopamine (6-OHDA)-induced experimental PD model. Rebamipide was given to adult male albino rats of Charles-Foster strain in 20, 40, and 80 mg/kg (R-20, R-40, and R-80) oral dose twice daily for 24 days (day 4 to day 27) after 6-OHDA intrastriatal injection. The drug inhibited 6-OHDA-induced motor deficits and nigral α-synuclein aggregates in dose-dependent manner. R-40 and R-80 dose dependently increased striatal mitochondrial complex I, II, IV, and V activities; mitochondrial bioenergetics; and nigral GCase activity. 6-OHDA-induced lipid peroxidation was decreased. Highest dose (R-80) also decreased apoptotic proteins and upregulated striatal dopamine concentration in 6-OHDA-induced hemiparkinson's rat model. Therefore, the anti-PD effect of rebamipide may involve stabilization of mitochondrial bioenergetics, enhancement of GCase enzymatic activity as well as decreased oxidative stress with α-synuclein pathology, and apoptosis in 6-OHDA-induced hemiparkinson's rat model. Hence, preclinical evidence indicates rebamipide to be a potential drug for management of PD.

Purinoceptors are present in neurons, microglia and oligodendrocytes and regulate dopamine (DA) release, striatal-related function and striatal neuronal and DA cells damage. Therefore, purinoceptors may be involved in the pathology of Parkinson's disease (PD) and purinergic antagonism may show neuroprotective effect. The study investigated the role of the non-selective purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2 ' , 4 ' -disulfonic acid (PPADS) and a selective purinergic receptor P2X7 receptor antagonist Brilliant Blue G (BBG) against 6-OHDA induced dopaminergic neurotoxicity in rats; while adenosine triphosphate (ATP) was used as a P2X receptor agonist. Behavioral parameters like spontaneous motor activity, narrow beam walk, footprint, bar catalepsy, grip strength and rotarod tests were performed to evaluate motor deficits in PD. Striatal DA contents were estimated as neurochemical measures of PD. Mitochondrial studies and oxidative status were assessed to investigate the mechanism of purinergic system antagonists. Involvement of purinergic receptors in apoptosis was assessed by expressing cytochrome-C, caspase-9 and caspase-3. Both the antagonists not only attenuated 6-OHDA induced motor deficits but also protected against 6-OHDA induced DA depletion in the striatum. Oxidative stress, mitochondrial integrity and dysfunction were attenuated by purinergic antagonists. Further, they attenuated mitochondrial-linked apoptosis as observed by a decrease in expression of cytochrome-C, caspase-9 and caspase-3. Therefore, purinoceptor antagonism shows neuroprotective effect in 6-OHDA induced dopamine toxicity through preservation of mitochondrial bioenergetics and anti-apoptotic activities.

Neonatal anoxia arises due to oxygen deprivation at the time of birth and results in life long neurodevelopmental deficits and sometimes may lead to death. The present study investigated the time dependent cortical mitochondrial dysfunction linked apoptosis and related sensorimotor deficits in neonates. Neonates after 30h to birth (P2) were subjected to anoxia of two episodes (10min in each) at a time interval of 24h by passing 100% N2 into an enclosed chamber as confirmed by pulse oximetry. Sensorimotor activities like reflex latency and hanging latency were carried out 24h after last anoxic episode i.e. from P4 (day-1) and continued up to P10 (day-7). Mitochondrial dysfunction after anoxia was evident by the decrease in respiration states, respiratory control ratio (RCR), antioxidant enzyme activity but an increase in oxidative stress and lipid peroxidation and alteration in mitochondrial membrane potential (MMP) at different time points (30min, 24h and day-7). A change in expression of Bcl-2 family proteins and opening of mitochondrial transition pore (mPTP) in terms of mitochondrial swelling was observed resulting in release of cytochrome-C which further activated intrinsic (mitochondrial) pathway of apoptosis through increased expression of caspase-9/3 as confirmed by flow cytometry. In conclusion, anoxia injury leads to progressive activation of mitochondrial events leading to increase in apoptotic cell death following secondary pathological insult. Therefore, strategies in limiting mitochondrial-linked apoptosis during the secondary insult input process may be useful in treatment of long term sensorimotor deficits following anoxia., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

Neonatal anoxia at the time of birth can lead to mitochondrial dysfunction and further neurodevelopmental abnormalities. The present study investigated the mitochondrial bioenergetics and associated sensorimotor changes in the anoxic neonatal rats. Rat pups after 30 h to birth (2 days) were subjected to anoxia of two episodes (10 min in each) at a time interval of 24 h by passing 100 % N2 into an enclosed chamber. Brain mitochondrial respiration was measured using clark type oxygen electrode. A significant decrease in brain respiratory control ratio (RCR; State III/IV respiration) at all-time points, complex I (24 h) and complex II (30 min, 6 and 24 h) enzyme activities indicated loss of mitochondrial integrity and function A significant increase in levels of nitric oxide was observed after second anoxic episode at all-time points. A significant change in sensorimotor activity in terms of increased reflex latency was observed 24 h after second episode in this model, which is an indication of loss of subcortical maturation. All the above changes were observed after second but not after the first anoxic exposure. Therefore, this anoxic model shows significant changes in mitochondrial bioenergetics, nitric oxide levels and sensorimotor effects after second episode of anoxia. This model may be helpful to evaluate mitochondrial targeted pharmacological intervention for the treatment of anoxia.

Mitochondria play a significant role in the pathophysiology of post-traumatic stress disorder (PTSD). Risperidone and paroxetine were evaluated for their effect on mitochondrial dysfunction and mitochondria-dependent apoptosis in discrete brain regions in modified stress re-stress (SRS) animal model of PTSD. Male rats were subjected to stress protocol of 2 h restraint and 20 min forced swim followed by halothane anesthesia on day 2 (D-2). Thereafter, rats were exposed to re-stress (forced swim) on D-8 and at 6-day intervals on D-14, D-20, D-26, and D-32. The rats were treated with risperidone (0.01, 0.1, and 1.0 mg/kg p.o.) and paroxetine (10.0 mg/kg p.o.) from D-8 to D-32. Risperidone at median dose and paroxetine ameliorated modified SRS-induced depressive-like symptom (increase in immobility period) in forced swim, anxiety-like behavior (decrease in percentage of open arm entries and time spent) in elevated plus maze and cognitive deficits (loss in spatial recognition memory) in Y-maze tests on D-32. Risperidone, but not paroxetine, attenuated modified SRS-induced decreases in plasma corticosterone levels. Risperidone ameliorated increase in the activity of mitochondrial respiratory complex (I, II, IV, and V), decreases in the levels of mitochondrial membrane potential, cytochrome-C and caspase-9 in the hippocampus, hypothalamus, pre-frontal cortex, and amygdala. However, both drugs attenuated modified SRS-induced increase in the number of apoptotic cells and caspase-3 levels in all the brain regions indicating anti-apoptotic activity of these drugs. Hence, these results suggest that anti-apoptotic activity could be a common mechanism for anti-PTSD-like effect irrespective of the pathways of apoptosis in the modified SRS model.

Ethnopharmacological Relevance: Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities., Aim of the Study: The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit., Materials and Methods: CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively., Results: Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities., Conclusion: The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and mitochondrial bioenergetics by shilajit indicates mitochondria as a potential target for treatment of CFS., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Neonatal asphyxia is a primary contributor to neonatal mortality and neuro-developmental disorders. It progresses in two distinct phases, as initial primary process and latter as the secondary process. A dynamic relationship exists between excitotoxicity and mitochondrial dysfunction during the progression of asphyxic injury. Study of status of glutamate and mitochondrial function in tandem during primary and secondary processes may give new leads to the treatment of asphyxia. Neonatal asphyxia was induced in rat pups on the day of birth by subjecting them to two episodes (10min each) of anoxia, 24h apart by passing 100% N(2) into an enclosed chamber. The NMDA antagonist ketamine (20mg/kg/day) was administered either for 1 day or 7 days after anoxic exposure. Tissue glutamate and nitric oxide were estimated in the cerebral cortex, extra-cortex and cerebellum. The mitochondria from the above brain regions were used for the estimation of malondialdehyde, and activities of superoxide dismutase and succinate dehydrogenase. Mitochondrial membrane potential was evaluated by using Rhodamine dye. Anoxia during the primary process increased glutamate and nitric oxide levels; however the mitochondrial function was unaltered in terms of succinate dehydrogenase and membrane potential. Acute ketamine treatment reversed the increase in both glutamate and nitric oxide levels and partially attenuated mitochondrial function in terms of succinate dehydrogenase activity. The elevated glutamate and nitric oxide levels were maintained during the secondary process but however with concomitant loss of mitochondrial function. Repeated ketamine administration reversed glutamate levels only in the cerebral cortex, where as nitric oxide was decreased in all the brain regions. However, repeated ketamine administration was unable to reverse anoxia-induced mitochondrial dysfunction. The failure of glutamate antagonism in the treatment of asphyxia may be due to persistence of mitochondrial dysfunction. Therefore, additionally targeting mitochondrial function may prove to be therapeutically beneficial in the treatment of asphyxia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mitochondrial dysfunction following spinal cord injury (SCI) may be critical for the development of secondary pathophysiology and neuronal cell death. Previous studies have demonstrated a loss of mitochondrial bioenergetics at 24 h following SCI. To begin to understand the evolution and study the contribution of mitochondrial dysfunction in pathophysiology of SCI, we investigated mitochondrial bioenergetics in the mid-thoracic region at 6, 12, and 24 h following contusion SCI. It is widely accepted that increased free radical generation plays a critical role in neuronal damage after SCI. Hence, to ascertain the role of free radicals in SCI-induced mitochondrial dysfunction, markers for oxidative damage, including nitrotyrosine (3-NT), lipid peroxidation byproduct (4-hydroxynonenal [HNE]), and protein oxidation (protein carbonyls) were quantified in the same samples of isolated mitochondria during the 24-h time course. The results demonstrate that a significant decline in mitochondrial function begins to occur 12 h post-injury and persists for a least 24 h following SCI. Furthermore, there was a progressive increase in mitochondrial oxidative damage that preceded the loss of mitochondrial bioenergetics, suggesting that free radical damage may be a major mitochondrial secondary injury process. Based on the present results, the temporal profile of mitochondrial dysfunction indicates that interventions targeting mitochondrial oxidative damage and dysfunction may serve as a beneficial pharmacological treatment for acute SCI.

Mitochondria are involved in the pathogenesis of post-traumatic stress disorder (PTSD). Phosphodiesterase-4 (PDE-4) regulates mitochondrial-dependent intracellular cAMP levels in neuropsychiatric disorders. Inhibition of PDE-4 with rolipram (RPM) has anxiolytic and psycho-mimetic properties. However, the role of PDE-4 inhibitor in PTSD remains unclear. Therefore, it may be useful in the treatment of comorbidities that resemble PTSD. The effects of RPM (PDE-4 inhibitor) and paroxetine (PAX) on mitochondrial dysfunction in the amygdala were investigated using the stress re-stress (SRS) model of PTSD. On day 2 (D-2), male rats were exposed to foot shock at intensity 2 mA for 10-second followed by halothane anesthesia. The rats were then subjected to re-stress of foot shock on D-8 to D-32 at 6-day intervals. RPM (0.5, 1, and 2 mg/kg) and PAX (10 mg/kg) treatments given orally from D-8 to D-32. RPM (1 and 2mg/kg) significantly attenuated SRS-induced PTSD-like symptoms like fear response, anxiety-like behavior, cognitive deficits and hypocorticosteronism. The SRS-induced decrease in mitochondrial respiratory complex (I, II, IV, and V) activity, respiratory control rate (RCR) and cAMP level in the amygdala were ameliorated by RPM. Further, sub-chronic treatment with RPM reduced the SRS-induced rise in ADP/ATP ratio in the amygdala. RPM ameliorated the SRS-induced alteration in mitochondrial membrane potential (MMP) and cytochrome-c levels in the amygdala. Thus, findings suggested that cAMP-dependent regulation of ADP/ATP ratio and mitochondrial function could be a potential mechanism for the anti-PTSD-like effect of RPM in the SRS model. [ABSTRACT FROM AUTHOR]

Circadian rhythms of physiology, behavior, and metabolism have an endogenous 24 h period that synchronizes with environmental cycles of light/dark and food availability. Alterations in light cycles are stressful and disrupt such diurnal oscillations. Recently, we witnessed a sudden rise in studies describing the mechanisms behind the interaction between the key characteristics of mitochondrial functions, peripheral clocks, and stress responses. To our knowledge, there is no study in the suprachiasmatic nuclei (SCN) describing the dysregulated mitochondrial bioenergetics under abnormal lighting conditions, which is common in today's modern world. Thus, we aimed to investigate the existence of daily changes in mitochondrial bioenergetics (respiratory control rate, RCR), mitochondrial abundance (mtDNA/nDNA), plasma corticosterone, and to test whether disturbances in the lighting conditions might influence such rhythms. To confirm this, mice were sacrificed, mitochondria were isolated from the suprachiasmatic nuclei in the brain and blood was collected, every 3 h at various time points zeitgeber time/circadian time, (0, 3, 6, 9, 12, 15, 18, 21, and 24 h) under 12:12 h light-dark (LD, 150 lux L: 0 lux D) cycle and chronic artificial dim lighting (LL, 5 lux: 5lux) conditions, of a 24 h period, respectively. Our results demonstrate the existence of robust daily rhythmicity in RCR, mtDNA/nDNA and plasma CORT under a normal LD cycle. However, these rhythms were significantly disrupted and clock genes expressions were dysregulated under chronic dim LL. Furthermore, mitochondrial abundance was significantly reduced during LL compared to their numbers under LD cycle. Our data demonstrate that the circadian clock regulates mitochondrial functions (RCR, number), essential for accomplishing daily energy demands and supply by the SCN neurons. Abnormal light exposure dysregulates mitochondrial functions in the SCN and may alter metabolism, resulting in obesity, diabetes, and other metabolic disorders. Therefore, properly designing lighting conditions in workplaces is essential to mitigate the adverse consequences of light on humans. [ABSTRACT FROM AUTHOR]

Mitochondria is an essential organelle; it produces 95% of the adenine triphosphate (ATP) of cells, their dysfunction is related to the pathogenesis of multiple diseases, such as diabetes mellitus, cardiovascular and neurological disorders. Various pharmacologic agents are known to target mitochondrial function. Moreover, the toxic side effects of multiple drugs used to treat diseases are related to the impairment of mitochondrial function. Thus, there is a need to develop a method to evaluate the effect of pharmacologic agents for their potential and side effects to identify effective mitochondrial-modulating agents. Therefore, the objective of this study was to develop and validate an ex-vivo method for studying the effect of pharmacologic agents on mitochondrial function and rescue of dysfunction. Dimethyl sulfoxide (DMSO) concentrations that drugs were soluble in and maintained mitochondrial function were determined. Metformin (MET) is a known mitochondrial complex-1 inhibitor tested for its ability to compromise mitochondrion function. Coenzyme Q10 (Q10) and Resveratrol (RSV), which are known to enhance mitochondrial function, were added alone and dose-dependent, tested for the ability to rescue metformin-induced mitochondrial dysfunction. Ex-vivo liver and brain mitochondrial function was assessed using an oxytherm Clark-type oxygen electrode. DMSO was found to be toxic above 10% and drugs insoluble below 5%. The addition of 0.5 mg/ml MET decreased liver and brain mitochondrial respiratory control rate (RCR). At the same time, Q10 improved RCR in normal mitochondria and a concentration-dependent manner in MET-induced dysfunctional mitochondria. RSV was added in the last step of the experiment to confirm that compromised function is due to MET. Hence this method can be used to screen pharmacological agents for their potential therapeutics or toxic effect on mitochondria. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that mitochondrial dysfunction plays a significant role in PTSD. However, the exact mechanism is still unclear. Mitochondrial dynamics could be one of the mechanisms, as it is crucial for mitochondrial homeostasis and is widely affected in traumatic situations. Mitochondrial dynamics regulate mitochondrial homeostasis via orexinergic receptors, and it is shown that antagonism of orexinergic receptors attenuates PTSD-like symptoms. Therefore, the present study aimed to determine how orexin antagonists affect mitochondrial dynamics in rats exhibiting PTSD-like symptoms. Using rats, a stress-re-stress (SRS) model with PTSD-like symptoms was established. On day 2 (D-2), the animals were exposed to variable stressors including 2 h of restraint followed by brief mild foot shock and exposure to 4%halothane. Foot shock was performed as a re-stress from D-8 to D-32 at six-day intervals. SRS exposure caused PTSD-like phenotype, hypothalamic-pituitary-adrenal axis dysfunction, activation of mammalian target of rapamycin (mTOR), and mitochondrial-fission-process-1 (MTFP-1). SRS-subjected rats exhibited enhanced expression of fission-regulating proteins, including dynamin-related protein-1 and mitochondrial-fission-protein-1 and reduced expression of fusion-regulating proteins, including optic-atrophy-1 and mitofusin-2, in the amygdala. TEM analysis revealed that SRS exposure further damaged the mitochondria. Treatment with suvorexant with rapamycin significantly mitigated PTSD-like symptoms and improved mitochondrial dynamics in SRS-exposed rats. However, their combination showed a more pronounced effect. Further, suvorexant in combination with rapamycin significantly mitigated mTOR and MTFP-1 activation. Sertraline attenuated PTSD-like symptoms without affecting SRS-induced activation of mTOR and disparity in mitochondrial dynamics. Suvorexant pharmacological effects on mitochondrial biogenesis also involve the mTOR pathway. The role of orexinergic pathway in SRS-induced mitochondrial mitophagy was not explored. Targeting both the orexinergic and mTOR pathways might exert a beneficial synergistic effect for treating PTSD. [Display omitted] • mTOR regulates MTFP1 translation and mitochondrial dynamics in SRS-exposed rats. • Suvorexant and rapamycin mitigate mTOR effect and stabilize the mitochondrial dynamics • Suvorexant and rapamycin ameliorate the SRS-induced mitochondrial damage in rats • SRS-induced PTSD-like phenotype ameliorated by suvorexant, rapamycin and sertraline • Suvorexant reduced the SRS-induced increased in plasma and CSF orexin-A level. [ABSTRACT FROM AUTHOR]

Abstract: Silymarin commonly known for its hepatoprotective effect is reported to show protection against 6-hydroxydopamine-induced neurotoxicity. Silibinin forms the major active constituent of silymarin. Therefore, the neuroprotective effect of silibinin (50, 100 and 200mg/kg) was evaluated in the unilaterally injected 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neurotoxicity in male rats. A battery of tests such as elevated plus maze (EPM), narrow beam walk, open field, bar catalepsy, grip strength, and foot print analysis was performed to evaluate the behavioral symptoms of striatal dopaminergic toxicity. Furthermore, the mechanism of action of silibinin was investigated by evaluating the mitochondrial complex enzyme activities, mitochondrial integrity and oxidative status. Striatal caspase-3 and NFκB were expressed to evaluate the effect of silibinin on apoptosis and inflammation respectively. Silibinin (100 and 200mg/kg) protected against MPP+-induced dopamine depletion in striatum. Silibinin reversed MPP+-induced decrease in transfer latency indicating memory consolidation in the EPM test. Silibinin (100 and 200mg/kg) attenuated MPP+-induced motor deficits, such as fine motor movements and gait. MPP+-induced mitochondrial dysfunction, loss of integrity and oxidative stress were attenuated by silibinin. Silibinin decreased striatal caspase-3 and NFκB expression indicating potential anti-apoptotic and anti-inflammatory effects respectively. Hence, silibinin exhibited neuroprotective effect in the MPP+ induced striatal toxicity augmenting dopamine levels. The mechanism of action may be linked to maintenance of mitochondrial bioenergetics and integrity apart from anti-apoptotic and anti-inflammatory activities. [Copyright &y& Elsevier]