Therapeutic Potential of Catechin as an IKK-ß Inhibitor for the Management of Arthritis: In vitro and In vivo Approach.

Background: Rheumatoid arthritis (RA) is associated with increased levels of cytokines, for instance, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and interleukin-1 (IL-1), which exhibit potent pro-inflammatory effects and are contributing factors to disease progression. A range of cytokines, cell adhesion molecules, and enzymes that are implicated in the debilitating effects of RA are transcribed by nuclear factor kappa. Objectives: The purpose of this research was to characterize the efficacy of "catechin" as an IkappaB kinase-beta (IKK-ß) inhibitor in collagen-induced arthritis (CIA) model in mice, as IKK-ß is crucial in the transmission of signal-inducible NF-κß activation. Methods: Arthritis was brought on in Bagg and Albino, but it is written BALB/c (BALB/c) male mice through subcutaneous immunization with bovine type II collagen on days 0 and 21. Catechin is given orally every day after the onset of the disease. Clinical evaluation of the prevalence and severity of the condition was done throughout the trial, and biochemical testing was done at the end (day 42). Results: In vitro findings of the study demonstrated catechin as a potent inhibitor of IKK-ß with Half maximal Inhibitory Concentration (IC50) values of 2.90 µM and 4.358 µM in IKK-ß and NF-κß transactivation activity assay, respectively. Furthermore, catechin (dose range of 10-100 mg/kg, p.o.) was effective in reducing disease incidence and clinical signs in a dose-dependent manner, with an Effective Dose for 50% of the population (ED50) value of 79.579 mg/kg. The findings of this study demonstrate dose-dependent efficacy in terms of both disease severity (clinical scoring) and inflammatory markers (biochemical evaluation of the serum and joints). Conclusions: IKK inhibitors are a prospective target for the creation of new therapeutics for arthritis and other inflammatory diseases because it has been suggested that this enzyme is crucial in the pathophysiology of RA. The finding of this study suggests that "catechin" represents a novel inhibitor of IKK-ß with promising anti-inflammatory activity.

Albumin-Coated Mesoporous Silica Nanoparticles of Docetaxel: Preparation, Characterization, and Pharmacokinetic Evaluation.

The potential of albumin-coated hollow mesoporous silica nanoparticles (A-HMSNs) to optimize the chemotherapeutic efficacy of docetaxel (DTX) was explored. The synthesized A-DTX-HMSNs had a nanometric size range, offered large surface area with numerous pores, and offered high drug entrapment and loading, that is, 79.18% ± 1.4% and 19.11% ± 1.30%, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry studies confirmed drug loading and the presence of albumin onto the developed systems, and the drug release followed Higuchi profile. A-HMSNs significantly enhanced the pharmacokinetic profile of DTX by eightfold vis-à-vis the pure DTX. The enhanced plasma levels (Cmax, Tmax, area under the curve), prolonged drug release, long circulation time, lower clearance, hemocompatability, and substantially higher drug loading offered by these nanocarriers inherit promise of a safer and efficacious formulation of DTX.

SIRT1 Promotes Neuronal Fortification in Neurodegenerative Diseases through Attenuation of Pathological Hallmarks and Enhancement of Cellular Lifespan.

Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.

Evaluation of sesamol and buspirone in stress induced anxiety in mice.

OBJECTIVES: The present study was designed to elucidate the effects of sesamol, buspirone and their combination in immobilization stress induced behavioral and biochemical alterations in mice. MATERIALS AND METHODS: Male Laca mice (divided into 10 groups with 6 animals each) were pre-treated with sesamol (5 and 10 mg/kg; p.o.), buspirone (5 and 10 mg/kg; p.o.) and combination of sesamol (5 and 10 mg/kg; p.o.) with buspirone (5 mg/kg; p.o.) for consecutive five days. On the 6(th) day, animals were immobilized for 6 h and various behavioral tests such as body weight, locomotor activity, mirror chamber test and elevated plus maze were carried out. Biochemical estimations such as lipid peroxidation and nitrite concentration, glutathione and catalase levels were done. Data was analyzed using One way ANOVA followed by Tukey's test (P < 0.05) was considered statistical significant. RESULTS: Immobilization stress significantly (P < 0.05) impaired body weight, locomotor activity, induced anxiety like behavioral and oxidative damage as compared to naοve animal. Pretreatment with sesamol (5 and 10 mg/kg; p.o.) and buspirone (5 and 10 mg/ kg; p.o.) significantly (P < 0.05) improved body weight, locomotor activity, and anxiety like behavior in mirror chamber as well as plus maze performance tasks and anti-oxidant like effect as evidenced by reduced lipid peroxidation, nitrite concentration and restoration of reduced glutathione and catalase activity as compared to control animals. Further, co- administration of sesamol (5 and 10 mg/kg) with buspirone (5 mg/kg) significantly (P < .05) potentiated the anti anxiety effects as compared to their effects alone. CONCLUSIONS: The present study suggests that combination of sesamol and buspirone potentiated the antianxiety effects against anxiety induced by immobilization stress and oxidative damage in mice.

Synergistical neuroprotection of rofecoxib and statins against malonic acid induced Huntington's disease like symptoms and related cognitive dysfunction in rats.

Malonic acid (MA) is a reversible inhibitor of succinate dehydrogenase (SDH) which induces mitochondrial dysfunction followed by secondary excitotoxicity and apoptosis due to generation of reactive oxygen species. Therapeutic potential of rofecoxib and statins have been well documented in several experimental models of neurodegenerative disorders, however, its exact mechanism of action is not known properly. Therefore, the present study is an attempt to investigate the effect of rofecoxib along with the statins against MA induced behavioural and biochemical alterations in rats. Single intrastriatal MA (6 µmol) significantly caused motor incordination, memory dysfunction and alteration in the antioxidant enzyme levels, mitochondrial enzyme complex (I, II, IV) activities, mitochondrial redox ratio and pro-inflammatory cytokine [tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] levels in the striatum as compared to the naive group. Fourteen days treatment with rofecoxib, atorvastatin, simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to control (MA treated group). However, the treatment of rofecoxib along with atorvastatin or simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to their individual effects. The results of the present study demonstrated that rofecoxib modulates the protective effects of statins against MA-induced neurobehavioral and related biochemical and cellular alterations in rats. This further provides evidence toward the involvement of neuroinflammatory cascade in the pathogenesis of Huntington's disease.

Potential role of licofelone, minocycline and their combination against chronic fatigue stress induced behavioral, biochemical and mitochondrial alterations in mice.

BACKGROUND: Chronic fatigue stress (CFS) is a common complaint among general population. Persistent and debilitating fatigue severely impairs daily functioning and is usually accompanied by combination of several physical and psychiatric problems. It is now well established fact that oxidative stress and neuroinflammation are involved in the pathophysiology of chronic fatigue and related disorders. Targeting both COX (cyclooxygenase) and 5-LOX (lipoxygenase) pathways have been proposed to be involved in neuroprotective effect. METHODS: In the present study, mice were put on the running wheel apparatus for 6 min test session daily for 21 days, what produced fatigue like condition. The locomotor activity and anxiety like behavior were measured on 0, 8(th), 15(th) and 22(nd) day. The brains were isolated on 22(nd) day immediately after the behavioral assessments for the estimation of oxidative stress parameters and mitochondrial enzyme complexes activity. RESULTS: Pre-treatment with licofelone (2.5, 5 and 10 mg/kg, po) and minocycline (50 and 100 mg/kg, po) for 21 days, significantly attenuated fatigue like behavior as compared to the control (rotating wheel activity test session, RWATS) group. Further, licofelone (5 and 10 mg/kg, po) and minocycline (50 and 100 mg/kg, po) drug treatments for 21 days significantly attenuated behavioral alterations, oxidative damage and restored mitochondrial enzyme complex activities (I, II, III and IV) as compared to control, whereas combination of licofelone (5 mg/kg) with minocycline (50 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect per se. CONCLUSION: The present study highlights the therapeutic potential of licofelone, minocycline and their combination against CFS in mice.

Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms.

Neuro-inflammation and oxidative stress plays a key role in the pathophysiology of Parkinson's disease (PD). Studies demonstrated that neuro-inflammation and associated infiltration of inflammatory cells into central nervous system are inhibited by 3-hydroxy-3-methyl glutaryl co-enzyme A (HMG-CoA) reductase inhibitors. Based on these experimental evidences, the present study has been designed to evaluate the neuroprotective effect of HMG-CoA reductase inhibitors (atorvastatin and simvastatin) against 6-hydroxydopamine (6-OHDA) induced unilateral lesion model of PD. In the present study, the animals were divided into nine groups (n=15 per group). Group I: Naive (without treatment); Group II: Sham (surgery performed, vehicle administered); Group III: Atorvastatin (20mg/kg); Group IV: Simvastatin (30 mg/kg); Group V: Control [Intrastriatal 6-OHDA (20 µg; single unilateral injection)]; Groups VI and VII: 6-OHDA (20 µg)+atorvastatin (10mg/kg and 20mg/kg) respectively; Groups VIII and IX: 6-OHDA (20 µg)+simvastatin (15 mg/kg and 30 mg/kg) respectively. Intrastriatal administration of 6-OHDA (20 µg; 4 µl of 5 µg/µl) significantly caused impairment in body weight, locomotor activity, rota-rod performance, oxidative defense and mitochondrial enzyme complex activity, and increase in the inflammatory cytokine levels (TNF-α and IL-6) as compared to naive animals. Atorvastatin (20mg/kg) and simvastatin (30 mg/kg) drug treatment significantly improved these behavioral and biochemical alterations restored mitochondrial enzyme complex activities and attenuated neuroinflammatory markers in 6-OHDA (20 µg) treated animals as compared to control group. The findings of the present study demonstrate the neuroprotective potential of statins in experimental model of 6-OHDA induced Parkinson like symptoms.

Targeting neuro-inflammatory cytokines and oxidative stress by minocycline attenuates quinolinic-acid-induced Huntington's disease-like symptoms in rats.

Recent experimental and clinical reports support the fact that the minocycline exhibits significant neuroprotective activity in neurodegenerative diseases. However, its mechanism of neuroprotection is still far from our understanding. Besides, minocycline does not always produce neuroprotective effect. Therefore, this study has been designed to explore the possible mechanism of minocycline in experimental model of HD in rats. Intrastriatal administration of quinolinic acid caused a significant reduction in body weight, motor dysfunction (impaired locomotor activity, rotarod performance, and beam walk test), oxidative damage (as evidenced by increase in lipid peroxidation, nitrite concentration, and depletion of super oxide dismutase and catalase), increased TNF-α and IL-6 levels as compared to the sham-treated animals. Minocycline (25, 50, and 100 mg/kg) treatment (for 21 days) significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, attenuated TNF-α and IL-6 levels as compared to quinolinic-acid (QA)-treated animals. This study provides evidence that minocycline might have neuroprotective effect against QA-induced Huntington-like behavioral, biochemical alterations, and neuroinflammation in rats.

Protective effect of HMG CoA reductase inhibitors against running wheel activity induced fatigue, anxiety like behavior, oxidative stress and mitochondrial dysfunction in mice.

BACKGROUND: Chronic fatigue stress (CFS) is an important health problem with unknown causes and unsatisfactory prevention strategies, often characterized by long-lasting and debilitating fatigue, myalgia, impairment of neuro-cognitive functions along with other common symptoms. The present study has been designed to explore the protective effect of statins against running wheel activity induced fatigue anxiety. METHODS: Male albino Laca mice (20-30 g) were subjected to swim stress induced fatigue in a running wheel activity apparatus. Atorvastatin (10, 20 mg/kg, po) and fluvastatin (5, 10 mg/kg, po) were administered daily for 21 days, one hour prior to the animals being subjected to running wheel activity test session of 6 min. Various behavioral tests (running wheel activity, locomotor activity and elevated plus maze test), biochemical parameters (lipid peroxidation, nitrite concentration, glutathione levels and catalase activity) and mitochondrial complex enzyme dysfunctions (complex I, II, III and IV) were subsequently assessed. RESULTS: Animals exposed to 6 min test session on running wheel for 21 days showed a significant decrease in number of wheel rotations per 6 min indicating fatigue stress like behavior. Treatment with atorvastatin (10 and 20 mg/kg) and fluvastatin (10 mg/kg) for 21 days significantly improved the behavioral alterations [increased number of wheel rotations and locomotor activity, and anxiety like behavior (decreased number of entries and time spent in open arm)], oxidative defence and mitochondrial complex enzyme activities in brain. CONCLUSION: Present study suggests the protective role of statins against chronic fatigue induced behavioral, biochemical and mitochondrial dysfunctions.

Possible GABAergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3-nitropropionic acid induced neurotoxicity.

Huntington's disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3-Nitropropionic acid induces selective striatal lesions in rodents and non-human primates. Therefore, the present study has been designed to elucidate the comparative mechanistic profile of gabapentin, lamotrigine and their interactions with GABAergic modulators against 3-Nitropropionic acid induced neurotoxicity. Systemic 3-Nitropropionic acid (10 mg/kg) administration for 14 days significantly reduced body weight, locomotor activity, grip strength, oxidative defense (LPO, nitrite, SOD and catalase) and impaired mitochondrial complex enzyme (I, II, IV and MTT assay) activities in the striatum. 3-Nitropropionic acid treatment also increased TNF-α level in the striatum. Gabapentin (50 and 100 mg/kg) and lamotrigine (10, 20 and 40 mg/kg) treatments significantly restored behavioural, oxidative defense and mitochondrial complex enzyme activities and proinflammatory markers (TNF-α) as compared to 3-Nitropropionic acid treated group. Systemic picrotoxin (1 mg/kg) pretreatment with sub effective dose of gabapentin (50 mg/kg) or lamotrigine (20mg/kg) significantly attenuated their protective effect. Further, GABA (50 mg/kg) and/or muscimol (0.05 mg/kg) pretreatment with sub effective dose gabapentin (50 mg/kg) and lamotrigine (20 mg/kg) significantly potentiated their protective effects which were significant as compared to their effect alone. The results of the present study suggest that a GABAergic mechanism is involved in the protective effect of gabapentin and lamotrigine against 3-Nitropropionic acid induced neurotoxicity.

Effect of nitric oxide in protective effect of melatonin against chronic constriction sciatic nerve injury induced neuropathic pain in rats.

Developing a successful treatment strategy for neuropathic pain has remained a challenge among researcher and clinicians. Various animal models have been employed to understand the pathogenic mechanism of neuropathic pain in experimental animals. The present study was designed to explore the possible nitric oxide mechanism in the protective effect of melatonin against chronic constriction injury (CCI) of sciatic nerve in rats. Following chronic constriction injury, various behavioral tests (thermal hyperalgesia, cold allodynia) and biochemical parameters (lipid peroxidation, reduced glutathione, catalase, and nitrite) were assessed in sciatic nerves. Drugs were administered for 21 consecutive days from the day of surgery. CCI significantly caused thermal hyperalgesia, cold allodynia and oxidative damage. Chronic administration of melatonin (2.5 or 5 mg/kg, ip) significantly attenuated hyperalgesia, cold allodynia and oxidative damage in sciatic nerves as compared to CCI group. Further, L-NAME (5 mg/kg) pretreatment with sub-effective dose of melatonin (2.5 mg/kg, ip) significantly potentiated melatonin's protective effect which was significant as compared to their individual effect per se. However, L-arginine (100 mg/kg) pretreatment with melatonin (2.5 mg/kg, ip) significantly reversed its protective effects. Results of the present study suggest the involvement of nitric oxide pathway in the protective effect of melatonin against CCI-induced behavioral and biochemical alterations in rats.

Role of LOX/COX pathways in 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats: protective effect of licofelone.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a degeneration of striatal neurons. The possible role of COX and lipoxygenase (LOX) pathways has been well-documented in the pathology of several neurodegenerative disorders including HD. Licofelone is a competitive inhibitor of COX-1- and COX-2 and 5-LOX isoenzymes. Therefore, the present study was designed to investigate possible neuroinflammatory and apoptotic mechanisms in the neuroprotective effect of licofelone against 3-nitropropionic acid (3-NP)-induced HD-like symptoms in rats. EXPERIMENTAL APPROACH: Rats were administered 3-NP (10 mg·kg⁻¹ day⁻¹, i.p.) for 14 days. Licofelone (2.5, 5 and 10 mg·kg⁻¹, p.o.) was given once a day, 1 h before 3-NP treatment for 14 days. Body weight and behavioural parameters (locomotor and rotarod activity) were assessed on the 1st, 5th, 10th and 15th day post-3-NP administration. Malondialdehyde, nitrite concentration, endogenous antioxidant enzymes (superoxide dismutase and catalase levels), mitochondrial enzyme complexes, pro-inflammatory compounds (TNF-α, IL-6, NF-κB), PGs (PGE2 and PGF(2α)) and caspase-3 activity were measured on day 15 in the striatum. KEY RESULTS: Systemic 3-NP treatment significantly reduced body weight, locomotor activity, oxidative defence, mitochondrial enzyme complex activities and increased TNF-α, IL-6, caspase-3 activity, NF-κB and PGE2 and PGF(2α) levels in the striatum. Licofelone (2.5, 5 and 10 mg·kg⁻¹) significantly attenuated the impairment in behavioural, biochemical and mitochondrial, pro-inflammatory and pro-apoptotic markers as compared with vehicle-treated group. CONCLUSIONS AND IMPLICATIONS: The results demonstrate the involvement of pro-inflammatory compounds and the apoptotic cascade in the neuroprotective effect of licofelone against 3-NP-induced neurotoxicity.

Suppressing inflammatory cascade by cyclo-oxygenase inhibitors attenuates quinolinic acid induced Huntington's disease-like alterations in rats.

AIMS: The aim of this study was to investigate the protective effects of cyclo-oxygenase inhibitors against quinolinic acid (QA) induced Huntington's disease-like alterations in rats. MAIN METHODS: Quinolinic acid (300 nmol) was administered intrastriatally into the striatum to induce Huntington's disease-like alteration. Cyclo-oxygenase inhibitors celecoxib (15 and 30 mg/kg) and meloxicam (10 and 20mg/kg) were given for 21 days. In behavioral assessment locomotor, rotarod, and balance beam walk performances were assessed. Oxidative stress, mitochondrial dysfunction, proinflammatory cytokines and caspase-3 were assessed on day 21 after behavioral assessments. KEY FINDINGS: Intrastriatal quinolinic acid (300 nmol) administration significantly altered the body weight, motor coordination, and induced oxidative damage (as indicated by the increase in lipid peroxidation and nitrite concentration) in the striatum as compared to sham group. Besides quinolinic acid (300 nmol) significantly depleted the mitochondrial enzyme complex levels and increased TNF-α, IL-6 and caspase-3 (marker of apoptotic cell death) levels in the striatum. Chronic treatment with celecoxib (15 and 30 mg/kg) significantly attenuated the quinolinic acid-induced behavioral and biochemical alterations, while meloxicam was able to reverse behavioral alterations at higher dose (20 mg/kg) as compared to the quinolinic acid treated group. Chronic treatment with the selective COX-2 inhibitors significantly restored the mitochondrial enzyme complex activities as well as attenuated TNF-α, IL-6 and caspase-3 levels as compared to the quinolinic acid treated group. SIGNIFICANCE: Results of the present study demonstrate the protective effect of cyclo-oxygenase inhibitors in the experimental models of Huntington's disease; and further provide evidence toward the involvement of neuroinflammatory cascade in the pathogenesis of Huntington's disease.

Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations.

Cyclo-oxygenase and lipoxygenase enzymes are involved in arachidonic acid metabolism. Emerging evidence indicates that cyclo-oxygenase and lipoxygenase inhibitors prevent neurodegenerative processes and related complications. Therefore, the present study has been designed to explore the neuroprotective potential of licofelone (dual COX-2/5-LOX inhibitor) against quinolinic acid induced Huntington like symptom in rats. Intrastriatal administration of quinolinic acid significantly caused reduction in body weight and motor function (locomotor activity, rotarod performance and beam walk test), oxidative defense (as evidenced by increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidant enzymes), alteration in mitochondrial enzyme complex (I, II and IV) activities, raised TNF-α level and striatal lesion volume as compared to sham treated animals. Licofelone (2.5, 5 and 10 mg/kg) treatment significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, mitochondrial enzyme complex activities and attenuated TNF-α level and striatal lesion as compared to control (quinolinic acid). The present study highlights that licofelone attenuates behavioral, biochemical and cellular alterations against quinolinic acid induced neurotoxicity and this could be an important therapeutic avenue to ameliorate the Huntington like symptoms.

Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats.

Huntington disease is a neurodegenerative disease with complex pathophysiology. Recently, role of neuroinflammation and interplay between various other cellular cascades have been suggested to be involved in pathophysiology of Huntington disease. Involvement of calcium overload mediated oxidative damage and excitotoxicity have been suggested to play a central role in quinolinic acid induced Huntington like symptoms. The present study has been carried out to investigate the neuroprotective effect of calcium channel blockers (verapamil and diltiazem) against quinolinic acid induced dysfunction in motor, biochemical and neuroinflammatory signaling in rats. Intrastriatal quinolinic acid administration leads to significant motor [locomotor (72% reduction), rotarod (55% reduction), balance beam walk performance] dysfunction coupled with the marked oxidative damage and increased neuroinflammatory markers [TNF-α (140%), IL-6 (115%), caspase-3(75%)] levels in striatum as compared to the sham treatment. Verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) drug treatment for 21days resulted in a significant improvement in the motor function (improvement in locomotor activity, rotarod and balance beam walk performance). Further, verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) treatment significantly attenuated oxidative damage, level of proinflammatory mediators (TNF-α IL-6 and caspase-3) in quinolinic acid treated animals. Results of the present study demonstrate that protective effect of these calcium channel blockers (verapamil, diltiazem) might be due to their inhibitory action on different neuroinflammatory pathways against quinolinic acid induced Huntington disease like symptoms in rats.

Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.

Novel protective mechanisms of antidepressants against 3-nitropropionic acid induced Huntington's-like symptoms: a comparative study.

Huntington's disease (HD) is characterized by progressive degeneration of neurons in the striatum, cortex and other parts of the brain, causing motor and cognitive dysfunction. 3-Nitropropionic acid (3-NP) is a well-known mycotoxin that significantly induces motor dysfunction in animals. Studies suggested the involvement of oxidative stress and nitric oxide mechanisms in HD pathogenesis. Clinical reports have also indicated the neuroprotective potential of antidepressants. Therefore, the present study has been designed to elucidate and compare the mechanistic role of different antidepressants (sertraline, venlafaxine, imipramine and trazodone) and their interaction with nitric oxide modulators if any, against 3-NP-induced neurotoxicity. Systemic 3-NP (10 mg/kg) administration for 14 days significantly reduced locomotor activity, body weight, motor coordination, oxidative defense and impaired mitochondrial complex enzyme activities in the striatum. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved behavioral, oxidative defense and mitochondrial complex enzyme activities as compared with the 3-NP-treated group. Systemic L-arginine (50 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly attenuated their protective effect. Similarly, L-nitro-arginine methyl ester (L-NAME) (10 mg/kg) pretreatment with sub-effective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) for 14 days significantly potentiated their protective effects which were significant as compared with their effect alone, respectively. The results of the present study suggest that a nitric oxide mechanism might be involved in their protective effect against 3-NP-induced neurotoxicity.

Possible nitric oxide modulation in protective effect of FK-506 against 3-nitropropionic acid-induced behavioral, oxidative, neurochemical, and mitochondrial alterations in rat brain.

FK-506 is an immunosuppressant being widely used for allograft rejection cases in the present clinical scenario. Recently, the neuroprotective effect of FK-506 has also been reported against a number of neurodegenerative diseases in rodents. This study was designed to explore the possible protective effect of FK-506 and its interaction with nitric-oxide modulators against 3-nitropropionic acid (3-NP)-induced behavioural, biochemical, neurochemical, and mitochondrial alterations in striatum, cortex, and hippocampus regions of the brain. Systemic administration of 3-nitropropionic acid produces Huntington-like symptoms in rats. 3-NP (10 mg/kg) treatment for 14 days impaired locomotor activity, grip strength, and body weight. 3-NP treatment significantly raised malondialdehyde, nitrite concentration, depleted antioxidant enzymes (SOD and catalase), and levels of bioamines (dopamine and norepinephrine) in striatum, cortex, and hippocampus areas of rat brain. Significant alterations in mitochondrial enzyme complexes (I, II, and IV) activities and mitochondrial redox activity have also been altered significantly by 3-NP. Pretreatment with FK-506 (0.5, 1, and 2 mg/kg) significantly reversed these behavioral, biochemical, and cellular alterations. L-arginine treatment with a subeffective dose FK-506 (1 mg/kg) reversed the protective effect of FK-506. However, L-NAME pretreatment with FK-506 (1 mg/kg) potentiated the protective effect of FK-506. The present study shows that FK-506 attenuates 3-NP-induced neurotoxicity and nitric-oxide modulation might be involved in its protective action.

Nitric oxide mechanism in the protective effect of antidepressants against 3-nitropropionic acid-induced cognitive deficit, glutathione and mitochondrial alterations in animal model of Huntington's disease.

Huntington's disease (HD), a basal ganglia disorder, is characterized not only by a spectrum of motor deficits, but also by emotional, cognitive and psychiatric manifestations. Cognitive impairment is one of the serious manifestations of this disease in the later stage of life. Although there is currently no cure for HD, there has been a surge of clinical trials involving patients with HD over the past 5 years. However, cognitive measures have generally been lacking from these trials. The beneficial effect of antidepressants in HD has been suggested in recent clinical trials. However, their mechanism of action is still not clear. Therefore, this study was designed to elucidate and compare the mechanistic role of different classes of antidepressants (sertraline, venlafaxine, imipramine and trazodone) against 3-nitropropionic acid (3-NP)-induced cognitive impairment, oxidative stress (glutathione) and mitochondrial dysfunction in rat hippocampus. Systemic treatment with 3-NP (10 mg/kg for 14 days) significantly impaired memory performance (both in the Morris water maze and elevated plus maze escape retention test), oxidative defence (glutathione redox status) and mitochondrial enzyme complex activities in rat hippocampus. Sertraline, venlafaxine, imipramine and trazodone treatments significantly improved performance in both cognitive tasks and glutathione redox status, and restored mitochondrial enzyme complex activities, as compared with the 3-NP treated group. L-arginine (50 mg/kg) pretreatment for 14 days together with a subeffective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) or trazodone (10 mg/kg) partially attenuated their protective effects. Further, G-nitro-L-Arginine-Methyl Ester (10 mg/kg) pretreatment together with subeffective dose of sertraline (10 mg/kg), venlafaxine (10 mg/kg), imipramine (10 mg/kg) and trazodone (10 mg/kg) significantly enhanced their efficacy. The results of this study suggest that nitric oxide modulation is involved in their protective effect of antidepressants against 3-NP induced cognitive dysfunction in rats.

Cyclosporine A attenuates 3-nitropropionic acid-induced Huntington-like symptoms in rats: possible nitric oxide mechanism.

Cyclosporine A is a well-known immunosuppressant drug that is currently used for prevention of allograft rejection. The current study was conducted to explore the therapeutic potential of cyclosporine A against 3-nitropropionic acid (3-NP)-induced neurotoxicity, an animal model of Huntington disease (HD). Systemic administration of 3-NP (10 mg/kg) for 14 days significantly impaired body weight, motor activity, biochemical parameters (raised lipid peroxidation, nitrite concentration, depletion of superoxide dismutase [SOD] and catalase), and mitochondrial enzymes. Cyclosporine A (2.5, 5, and 10 mg/kg) treatment significantly attenuated behavioral, biochemical, and cellular alterations. Furthermore, L-arginine pretreatment with cyclosporine A (5 mg/kg) significantly reversed the protective effect of cyclosporine A. However, L-nitro-arginine methyl ester (L-NAME; 10 mg/kg) pretreatment potentiated the protective effect of cyclosporine A (5 mg/kg). Study highlights the therapeutic potential of cyclosporine A in the treatment of HP. Study suggests that nitric oxide (NO) modulation is involved in the neuroprotective effect of cyclosporine A against 3-NP neurotoxicity.