Neuroprotective potential of azilsartan against cerebral ischemic injury: Possible involvement of mitochondrial mechanisms.

AIMS: Mitochondrial dysfunction is a major player in initiating the cellular cascades which lead to neuronal damage post cerebral ischemia. Angiotensin II Type 1 (AT1) receptor blockers are one of the most commonly employed antihypertensive drugs due to their good safety and efficacy profiles. This study was designed to investigate the neuroprotective potential of a newer AT1 receptor blocker azilsartan against global cerebral ischemia induced brain injury in Wistar rats and the possible involvement of mitochondrial restorative mechanism in its effect. METHODS: Bilateral common carotid artery occlusion (30min Ischemia and 48hr reperfusion) was performed in Wistar rats for the induction of global cerebral ischemia. Pre-treatment with azilsartan (2 and 4 mg/kg; p.o.) or coenzyme Q10 (20 and 40 mg/kg; p.o.) starting 7 days prior to BCCAO till the end of reperfusion was done. RESULTS: Azilsartan and coenzyme Q10 preserved the behavioral function (locomotor activity, rota rod performance and beam balance score), arrested oxidative stress (LPO, nitrite, GSH and SOD), decreased apoptotic damage (caspase-3), neuroinflammation (TNF-α), infarct area (TTC staining) and restored histological alterations (H&E staining) as compared to vehicle treatment. Maximum effect was seen when a combination of both drugs was administered. In addition, azilsartan was able to protect the activity of mitochondrial complexes and in combination with the ubiquitous electron carrier coenzyme Q10, it significantly preserved the mitochondrial respiratory function by stimulating the oxidative phosphorylation (oxygen consumption using clarke's electrode). CONCLUSIONS: These findings explicitly highlight neuroprotective properties of azilsartan against cerebral ischemia, possibly through mitochondrial mechanisms.

Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer's type in rats.

Alzheimer disease represents a major public health issue with limited therapeutic interventions. We explored the possibility of therapeutic approach by repurposing of tramadol in a sporadic animal model of Alzheimer's type. Streptozocin (STZ 3 mg/kg; bilaterally) was injected to male SD rats through intracerebroventricular (ICV) route. Drug treatment was started just after streptozocin administration and continued for 3 weeks. The rats were killed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and pre-frontal cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes activity and histological examination. Tramadol (5, 10 and 20 mg/kg, i.p.) was used as a treatment drug, and memantine (10 mg/kg, i.p.) was used as a standard. Tramadol significantly attenuated behavioral, biochemical, mitochondrial and histological alterations at low (5 mg/kg) and intermediate (10 mg/kg) dose, suggesting its neuroprotective potential in ICV-STZ-treated rats. Further, the neuroprotective effect of tramadol (10 mg/kg) was comparable to memantine (10 mg/kg). In conclusion, our results indicate the effectiveness of tramadol in preventing ICV-STZ-induced cognitive impairment as well as mito-oxidative stress. Further, these findings reveal the possibility of MOR agonist as a therapeutic approach for sporadic Alzheimer disease.

Potential drug targets and treatment of schizophrenia.

Schizophrenia is one of the most prevalent chronic psychiatric disorders that affect 1% of the world's population. Despite its societal burden, pathophysiology of schizophrenia remains poorly understood. Currently available drugs predominantly control positive symptoms, and often have no or poor control on negative and related cognitive symptoms, which strongly affect functional outcome in schizophrenia. The present article is an attempt to provide a critical review of recent hypothesis to understand pathophysiology of schizophrenia and to highlight exploitable molecular drug targets other than dopaminergic systems to treat and manage schizophrenia effectively.

Role of Glutathione-S-transferases in neurological problems.

INTRODUCTION: Role of Glutathione-S-transferases (GSTs) has been well explored in the cellular detoxification process, regulation of redox homeostasis and S-glutothionylation of target proteins like JNK, ASK1 etc. However, altered levels or functions of this enzyme or their subtypes have emerged in the development of several pathologies diseases such as Alzheimer's disease, Parkinson's disease, cancer and related conditions. Oxidative stress is one of the possible pathological events that contributes significantly to activation of degenerating cascades inside neuronal cells. The central nervous system is highly sensitive to oxidative stress because of low levels or capacities of antioxidant enzymes. The brain is highly metabolic in nature making it susceptible to oxidative stress. Areas covered: The present review provides a comprehensive overview of the multiple connections of GSTs within diverse neurological diseases including cancer. Furthermore, the authors have made significant efforts to discuss the regulation of different GST isoforms that have been associated with various pathological processes such as glioblastoma, Alzheimer's disease, Parkinson's disease, stroke and epilepsy. Expert opinion: Though GSTs have been one of the key areas of scientific research over the last few decades, much remains to be elucidated about their physiological functions as well as pathological involvement of GSTs and their polymorphic variants.

Astroglia acquires a toxic neuroinflammatory role in response to the cerebrospinal fluid from amyotrophic lateral sclerosis patients.

BACKGROUND: Non-cell autonomous toxicity is one of the potential mechanisms implicated in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). However, the exact role of glial cells in ALS pathology is yet to be fully understood. In a cellular model recapitulating the pathology of sporadic ALS, we have studied the inflammatory response of astroglia following exposure to the cerebrospinal fluid from ALS patients (ALS-CSF). METHODS: Various inflammatory markers including pro-inflammatory and anti-inflammatory cytokines, COX-2, PGE-2, trophic factors, glutamate, nitric oxide (NO), and reactive oxygen species (ROS) were analyzed in the rat astroglial cultures exposed to ALS-CSF and compared with the disease control or normal controls. We used immunofluorescence, ELISA, and immunoblotting techniques to investigate the protein expression and real-time PCR to study the messenger RNA (mRNA) expression. Glutamate, NO, and ROS were estimated using appropriate biochemical assays. Further, the effect of conditioned medium from the astroglial cultures exposed to ALS-CSF on NSC-34 motor neuronal cell line was detected using the MTT assay. Statistical analysis was carried out using one-way ANOVA followed by Tukey's post hoc test, or Student's t test, as applicable. RESULTS: Here, we report that the ALS-CSF enhanced the production and release of inflammatory cytokines IL-6 and TNF-α, as well as COX-2 and PGE-2. Concomitantly, anti-inflammatory cytokine IL-10 and the beneficial trophic factors, namely VEGF and GDNF, were down-regulated. We also found impaired regulation of glutamate, NO, and ROS in the astroglial cultures treated with ALS-CSF. The conditioned medium from the ALS-CSF exposed astroglial cultures induced degeneration in NSC-34 cells. CONCLUSIONS: Our study demonstrates that the astroglial cells contribute to the neuroinflammation-mediated neurodegeneration in the in vitro model of sporadic ALS.

Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction.

RATIONALE: The therapeutic potential of berberine has been well documented in various neurological problems. However, the neurological mechanism of berberine remains untapped in the light of its P-glycoprotein (P-gp)-mediated gut efflux properties responsible for reduced bioavailability. Verapamil, a well known L-type calcium channel blocker, has additional inhibitory activity against P-gp efflux pump. Thus, there is a strong scientific rationale to explore the interaction of berberine with verapamil as a possible neuroprotective strategy. OBJECTIVE: The present study was designed to evaluate the effect of berberine, verapamil, and their combination on behavioral alterations, oxidative stress, mitochondrial dysfunction, neuroinflammation, and histopathological modifications in intracerebroventricular streptozocin (ICV-STZ)-induced sporadic dementia of Alzheimer's type in rats. METHODS: Single bilateral ICV-STZ (3 mg/kg) administration was used as an experimental model of sporadic dementia of Alzheimer's type. RESULTS: Berberine (25, 50, and 100 mg/kg, oral gavage) or verapamil (2.5 and 5 mg/kg, intraperitoneally) were used as treatment drugs, and memantine (5 mg/kg, intraperitoneally) was used as a standard. Berberine and verapamil significantly attenuated behavioral, biochemical, cellular, and histological alterations, suggesting their neuroprotective potential. Further, treatment of berberine (25 and 50 mg/kg) with verapamil (2.5 and 5.0 mg/kg) combinations respectively significantly potentiated their neuroprotective effect which was significant as compared to their effect per se in ICV-STZ-treated animals. CONCLUSION: The augmentative outcome of verapamil on the neuroprotective effect of berberine can be speculated due to the inhibition of P-gp efflux mechanism and the prevention of calcium homeostasis alteration. Additionally, anti-inflammatory and antioxidant effects of both berberine and verapamil could also contribute in their protective effect.

Current knowledge and pharmacological profile of berberine: An update.

Berberine, a benzylisoquinoline alkaloid, occurs as an active constituent in numerous medicinal plants and has an array of pharmacological properties. It has been used in Ayurvedic and Chinese medicine for its antimicrobial, antiprotozoal, antidiarrheal and antitrachoma activity. Moreover, several clinical and preclinical studies demonstrate ameliorative effect of berberine against several disorders including metabolic, neurological and cardiological problems. This review provides a summary regarding the pharmacokinetic and pharmacodynamic features of berberine, with a focus on the different mechanisms underlying its multispectrum activity. Studies regarding the safety profile, drug interactions and important clinical trials of berberine have also been included. Clinical trials with respect to neurological disorders need to be undertaken to exploit the beneficiary effects of berberine against serious disorders such as Alzheimer's and Parkinson's disease. Also, clinical studies to detect rare adverse effects of berberine need to be initiated to draw a complete safety profile of berberine and strengthen its applicability.

Therapeutic potential of mGluR5 targeting in Alzheimer's disease.

Decades of research dedicated toward Alzheimer's disease (AD) has culminated in much of the current understanding of the neurodegeneration associated with disease. However, delineating the pathophysiology and finding a possible cure for the disease is still wanting. This is in part due to the lack of knowledge pertaining to the connecting link between neurodegenerative and neuroinflammatory pathways. Consequently, the inefficacy and ill-effects of the drugs currently available for AD encourage the need for alternative and safe therapeutic intervention. In this review we highlight the potential of mGluR5, a metabotropic glutamatergic receptor, in understanding the mechanism underlying the neuronal death and neuroinflammation in AD. We also discuss the role of mGlu5 receptor in mediating the neuron-glia interaction in the disease. Finally, we discuss the potential of mGluR5 as target for treating AD.

Neurobehavioral toxicity in progeny of rat mothers exposed to methylmercury during gestation.

INTRODUCTION: Methylmercury (MeHg) is recognized as one of the most hazardous environmental pollutants. This may be a concern to long-term consumption of contaminated fish and seafood for health risk to pregnant women and their children. AIM: An animal study was conducted to assess the effect of MeHg exposure on rodent offspring following in utero exposure. METHODS: Pregnant Wister rats were treated by gavage with MeHg at dose levels of 0.5, 1.0 and 2.0 mg/kg/day from gestation day (GD) 5 till parturition, and then were allowed to deliver. RESULTS: Dams treated with 2.0 mg/kg/day MeHg group showed signs of toxicity such as gait alterations and hyperactivity resulting in the failure to deliver sustainable viable pups. MeHg had significant effects on body weight gain of dams during GD 5 till parturition. MeHg had no significant effects on the ages of physical developments such as pinna detachment, incisor eruptions or eye opening as well as alter cliff avoidance, surface righting, swimming ontogeny, startle reflex, pivoting, negative geotaxis, or forelimb and hindlimb grip strength in either sex. Exposure to 1.0 mg/kg/day MeHg treatment group prolonged gestation period, retard mid-air righting in male pups, shortened forelimb grip strength measured on rotating rod in either sex and enhanced open field behaviour in male pups. Data obtained from Functional Observation Battery (FOB) also revealed impairment of neuromotor performance in male pups. The male pups appeared to be more susceptible than the female pups. CONCLUSION: Overall, the dose level of MeHg in the present study produced a few adverse effects on the neurobehavioral parameters, and it may alter neuromotor performance of the male pups.

Influence of gestational exposure on the effects of prenatal exposure to methyl mercury on postnatal development in rats.

Fish and other aquatic organisms are important source of dietary proteins for the human population. Fish meat, however, is contaminated with methyl mercury (MeHg), a potent neurotoxin. The well known Minamata and Niigata epidemic outcomes in Japan have raised the awareness of the health risk resulting from consumption of fish (and shellfish) from water basins polluted with industrial wastes containing mercury. In the present study, pregnant rat dams were exposed to environmental toxic elements--methyl mercury, 1000-1200 h, daily from the fifth gestation day (GD5) till parturition. Three groups of animals were given, by gavages, MeHg (0.5, 1.0 and 2.0 mg/kg/day) and control group received 0.9% saline at the same time. All animals were allowed to deliver and wean their offspring. Pups were evaluated for early development effects. There was a significant effect of treatment on somatic growth such as reduction in percentage of maternal weight gain (20.62%) at higher dose level whereas there was no change in percentage of live birth (100.00%) with 0.5 and 1.0 mg/kg dose treatment groups. There was a significant increase in the percentage of resorption (100.00%) per litter with 2.0 mg/kg/day MeHg dose. Average gestation length (days) and percentage resorption per litter or percentage foetuses/malformations per litter were not affected at 0.5 and 1.0 mg/kg/day dose level. The results of the study confirmed the high-teratogenic potential of MeHg and the need of payng increased attention to MeHg concerning its exogenous use during pregnancy.

Differential role of cyclooxygenase isozymes on neuronal density in hippocampus CA1 region of intracerebroventricular streptozotocin treated rat brain.

Intracerebroventricular (ICV) administration of streptozotocin (STZ) causes degeneration of hippocampal neurons through unknown mechanisms that further lead to dementia. On assumption that enzyme cyclooxygenase (COX), which catalyzes the production of pro-inflammatory prostaglandins, may be involved in ICV-STZ induced neurodegeneration, the present study was designed to investigate the effects of chronic treatment with selective inhibitor of COX-1, COX-2 or COX-3 on hippocampal neuronal density in ICV-STZ treated rats. Drugs were administered daily for 21 days, intraperitoneally, in sham control as well as ICV-STZ treated rats. After 21 days of treatment, rats were sacrificed and histological changes were observed in Cornus Ammonis (CA)-1 region of hippocampus at light microscopic level. Histopathological evaluation showed that valeryl salicylate (selective COX-1 inhibitor; 5 and 10 mg/kg; i.p.) and etoricoxib (selective COX-2 inhibitor; 5 and 10 mg/kg; i.p.) significantly increased the survival of hippocampus CA1 neurons in a dose dependent manner. On the contrary, phenacetin (selective COX-3 inhibitor; 20 and 40 mg/kg; i.p.) treatment had no effect on reduced neuronal density in ICV-STZ treated rats. In summary, these findings provide the first comprehensive description about the differential role of COX isozymes in ICV-STZ induced neuronal death in hippocampal CA1 regions of the rat brain.

Peroxisome proliferator-activated receptor-α activation attenuates 3-nitropropionic acid induced behavioral and biochemical alterations in rats: possible neuroprotective mechanisms.

Peroxisome proliferators activated receptor is regarded as potential therapeutic targets to control various neurodegenerative disorders. However, none of the study has elucidated its effect in the treatment of Huntington's disease. We explored whether peroxisome proliferators activated receptor-α agonist may attenuate various behavioral and biochemical alterations induced by systemic administration of 3-nitropropionic acid (3-NP), an accepted experimental animal model of Huntington's disease phenotype. Intraperitoneal administration of 3-NP (20mg/kg., i.p.) for 4days in rats produced hypolocomotion, muscle incoordination, and cognitive dysfunction. Daily treatment with fenofibrate (100 or 200mg/kg., p.o.), 30min prior to 3-NP administration for a total of 4days, significantly improved the 3-NP induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-NP administration significantly increased oxidative and nitrosative stress (increase lipid peroxidation, protein carbonyls and nitrite level), lactate dehydrogenase activity whereas, decreased the activities of catalase, superoxide dismutase, reduced glutathione, and succinate dehydrogenase. Fenofibrate treatment significantly attenuated oxidative damage, cytokines and improved mitochondrial complexes enzyme activity in brain. In the present study, MK886, a selective inhibitor of peroxisome proliferators activated receptor-α was employed to elucidate the beneficial effect through either receptor dependent or receptor independent neuroprotective mechanisms. Administration of MK886 (1mg/kg, i.p.) prior to fenofibrate (200mg/kg, p.o.) abolished the effect of fenofibrate. The results showed that receptor dependent neuroprotective effects of fenofibrate in 3-NP administered rats provide a new evidence for a role of PPAR-α activation in neuroprotection that is attributed by modulating oxidative stress and inflammation.