Antidepressant-like effect of sodium orthovanadate in a mouse model of chronic unpredictable mild stress.

Depression is a psychiatric disorder characterized by low-esteem, anhedonia, social deficit, and lack of interest. Decreased brain-derived neurotrophic factor (BDNF) and impaired tropomyosin kinase B receptor (TrkB receptor) signaling are associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and enzyme-linked immunosorbent assay (ELISA) for BDNF were performed. Body weight was measured every week. CUMS induced depressive-like behavior was found to be associated with increased oxidative stress in the brain and serum corticisterone with subsequent reduction of BDNF. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor already reported to elevate BDNF levels, was used as the test drug. Sodium orthovanadate (5 mg/kg, 10 mg/kg) and fluoxetine (FLX-10 mg/kg) was given to mice orally for 21days before 30 min of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg demonstrated significant results in the present study characterized by decreased malondialdehyde levels (MDA/LPO), NO levels, and increased GSH level and SOD activity in both the cortex and hippocampus. Besides, ELISA has revealed the significant elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) as compared to the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels observed with SOV (5 & 10 mg/kg), FLX-10 mg/kg, FLX (10 mg/kg) + SOV (5 mg/kg); and SOV-10 mg/kg per-se treatment and elevated BDNF level with SOV (5 & 10 mg/kg), FLX-10 mg/kg were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effects or prevent stress-induced anhedonia and so further molecular mechanisms are warranted for clinical translation.

IDO-1 inhibition protects against neuroinflammation, oxidative stress and mitochondrial dysfunction in 6-OHDA induced murine model of Parkinson's disease.

Parkinson's disease (PD), a common neurodegenerative motor disorder characterized by striatal dopaminergic neuronal loss and localized neuroinflammation in the midbrain region. Activation of microglia is associated with various inflammatory mediators and Kynurenine pathway (KP) being one of the major regulator of immune response, is involved in the neuroinflammatory and neurotoxic cascade in PD. In the current study, 1-Methyltryptophan (1-MT), an Indolamine-2,3-dioxygenase-1 (IDO-1) inhibitor was tested at different doses (2.5 mg/kg, 5 mg/kg and 10 mg/kg) for its effect on behavioral parameters, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurotransmitter levels, biochemical and behavioral alterations in unilateral 6-OHDA (3 µg/µL) murine model of PD. The results showed improved locomotion in open field test and motor coordination in rota-rod, reduced oxidative stress, neuroinflammatory markers (TNF-α, IFN-γ, IL-6), mitochondrial dysfunction and neuronal apoptosis (caspase-3). Also, restoration of neurotransmitter levels (dopamine and homovanillic acid) in the striatum and increased striatal BDNF levels were observed. Overall findings suggest that 1-MT could be a potential candidate for further studies to explore its possibility as an alternative in the pharmacotherapy of PD.

Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington's disease through inhibition of NF-κB mediated neuroinflammatory markers and activation of cAMP/CREB/BDNF signaling pathway.

Huntington's disease (HD) is a progressive neurodegenerative and hyperkinetic movement disorder. Decreased activity of cAMP-responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in HD. The present study has been designed to explore the possible role of roflumilast against qunilonic acid (QA) induced neurotoxicity in rats intending to investigate whether it inhibits the neuroinflammatory response through activation of the cAMP/CREB/BDNF signaling pathway. QA was microinjected (200 nmol/2 µl, bilaterally) through the intrastriatal route in the stereotaxic apparatus. Roflumilast (0.5, 1, and 2 mg/kg, orally) once-daily treatment for 21 days significantly improved locomotor activity in actophotometer, motor coordination in rotarod, and impaired gait performance in narrow beam walk test. Moreover, roflumilast treatment significantly attenuated oxidative and nitrosative stress (p < 0.05) through attenuating lipid peroxidation nitrite concentration and enhancing reduced glutathione, superoxide dismutase, and catalase levels. Furthermore, roflumilast also significantly decreased elevated pro-inflammatory cytokines like TNF-α (p < 0.01), IL-6 (p < 0.01), IFN-γ (p < 0.05), NF-κB (p < 0.05) and significantly increased BDNF(p < 0.05) in the striatum and cortex of rat brain. The results further demonstrated that roflumilast effectively increased the gene expression of cAMP(p < 0.05), CREB(p < 0.05) and decreased the gene expression of PDE4 (p < 0.05) in qRT-PCR. These results conclusively depicted that roflumilast could be a potential candidate as an effective therapeutic agent in the management of HD through the cAMP/CREB/BDNF signaling pathway.

Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer's-like dementia via targeting neuroinflammatory and IRS-1/PI3K/AKT/GSK-3ß pathway.

Alzheimer's disease (AD) is prevalent in old age people and is one of the most common brain diseases. Brain insulin resistance, neuroinflammation, oxidative stress, and mitochondrial and cholinergic dysfunction are key features of the disease. In our study, streptozotocin (STZ) in a dose of 3 mg/kg was injected in male Wistar rats bilaterally through the intracerebroventricular (ICV) route on stereotaxic apparatus. Chromium picolinate (CrPic) was tested at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, while rivastigmine (2 mg/kg) was used as reference standard drug. Cognitive dysfunction induced by STZ was assessed by behavioral tests like Morris water maze and novel object recognition test. Treatment with CrPic revealed attenuation of cognitive deficit. This was confirmed by behavioral tests, biochemical estimations of antioxidant enzymes, oxidative stress, nitrosative stress, and cholinergic and mitochondrial activity. CrPic did not change AchE activity significantly. STZ-induced neuroinflammation evident by increased TNF-α, IL-6, and CRP levels was also significantly decreased by CrPic. Dysfunctional insulin signaling after ICV-STZ was demonstrated by reduced IRS-1, PI3K, AKT, BDNF gene expression, and increased GSK-3ß, NF-κB gene expression with the help of qRT-PCR. CrPic treatment produced an improvement in insulin signaling revealed by increased gene expression of IRS-1, PI3-K, AKT, BDNF, and decreased gene expression of GSK-3ß and NF-κB. It was concluded that CrPic reversed AD pathology revealed by improved memory, reduced oxidative stress, neuroinflammation, mitochondrial dysfunction, and upregulated insulin signaling.

Modeling of antipsychotic-induced metabolic alterations in mice: An experimental approach precluding psychosis as a predisposing factor.

Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis.

Naringenin protects against oxido-inflammatory aberrations and altered tryptophan metabolism in olfactory bulbectomized-mice model of depression.

Oxido-inflammatory aberrations play a substantial role in the pathophysiology of depression. Oxido-inflammatory stress increases catabolism of tryptophan into kynurenine which leads to imbalance in kynurenine and serotonin levels in the brain. Naringenin a flavonoid, has been reported to possess antidepressant property by restoring serotonin and noradrenaline levels in the brain. Its effects on oxido-inflammatory aberrations in depression has not been investigated. With this background, the present study was designed to investigate the antidepressant-like potential of naringenin in olfactory bulbectomy (OBX)-induced neuroinflammation, oxidative stress, altered kynurenine pathway, and behavioural deficits in BALB/c mice. OBX-mice showed depression-like behavioural alterations characterized by hyperactivity in open field, increased immobility time in forced swim test and decreased sucrose preference. After 14 days, OBX-mice were treated by gavage with naringenin (25, 50 and 100 mg/kg) and fluoxetine (5 mg/kg) for two weeks. Naringenin significantly ameliorated depression-like behavioural alterations. Naringenin significantly restored corticosterone levels in serum and antioxidant enzymes (Catalase, SOD GSH), nitrite and MDA in cerebral cortex and hippocampus showing its anti-stress and antioxidant property. Naringenin also significantly decreased elevated pro-inflammatory cytokines like IL-1ß, IL-6, TNF-α and NF-Òß levels. Naringenin also significantly increased neurotrophic growth factor like BDNF. Naringenin reversed altered levels of tryptophan, serotonin, 5-Hydroxyindole acetic acid and kynurenine in hippocampus and cortex. A positive correlation was found between KYN/TRP ratio and proinflammatory parameters while endogenous antioxidants were negatively correlated. In conclusion, naringenin showed potent neuroprotective effect in depression comparable to the fluoxetine by restoring alterations in kynurenine pathway via its antioxidant and anti-inflammatory potential.

TRP channels: potential drug target for neuropathic pain.

Neuropathic pain is a debilitating disease which affects central as well as peripheral nervous system. Transient receptor potential (TRP) channels are ligand-gated ion channels that detect physical and chemical stimuli and promote painful sensations via nociceptor activation. TRP channels have physiological role in the mechanisms controlling several physiological responses like temperature and mechanical sensations, response to painful stimuli, taste, and pheromones. TRP channel family involves six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) which are expressed in pain sensing neurons and primary afferent nociceptors. They function as transducers for mechanical, chemical, and thermal stimuli into inward currents, an essential first step for provoking pain sensations. TRP ion channels activated by temperature (thermo TRPs) are important molecular players in acute, inflammatory, and chronic pain states. Different degree of heat activates four TRP channels (TRPV1-4), while cold temperature ranging from affable to painful activate two indistinctly related thermo TRP channels (TRPM8 and TRPA1). Targeting primary afferent nociceptive neurons containing TRP channels that play pivotal role in revealing physical stimuli may be an effective target for the development of successful pharmacotherapeutics for clinical pain syndromes. In this review, we highlighted the potential role of various TRP channels in different types of neuropathic pain. We also discussed the pharmacological activity of naturally and synthetically originated TRP channel modulators for pharmacotherapeutics of nociception and neuropathic pain.

Niflumic acid, a TRPV1 channel modulator, ameliorates stavudine-induced neuropathic pain.

TRP channels have been discovered as a specialized group of somatosensory neurons involved in the detection of noxious stimuli. Desensitization of TRPV1 located on dorsal root and trigeminal ganglia exhibits analgesic effect and makes it potential therapeutic target for treatment of neuropathic pain. With this background, the present study was aimed to investigate the protective effect of niflumic acid, a TRPV1 modulator, on stavudine (STV)-induced neuropathic pain in rats. Stavudine (50 mg/kg) was administered intravenously via tail vein in rats to induce neuropathic pain. Various behavioral tests were performed to access neuropathic pain (hyperalgesia and allodynia) on 7th, 14th, 21st, and 28th days. Electrophysiology (motor nerve conduction velocity; MNCV) and biochemical estimations were conducted after 28th day. Niflumic acid (10, 15, and 20 mg/kg) was administered intraperitoneally and evaluated against behavioral, electrophysiological (MNCV), and biochemical alterations in stavudine-treated rats. Pregabalin (30 mg/kg) was taken as reference standard and administered intraperitoneally. Four weeks after stavudine injection, rats developed behavioral, electrophysiological (MNCV), and biochemical (oxidative, nitrosative stress, and inflammatory cytokines, TRPV1) alterations. Niflumic acid restored core and associated symptoms of peripheral neuropathy by suppressing oxidative-nitrosative stress, inflammatory cytokines (TNF-α, IL-1ß) and TRPV1 level in stavudine-induced neuropathic pain in rats. Pharmacological efficacy of niflumic acid (20 mg/kg) was equivalent to pregabalin (30 mg/kg). In conclusion, niflumic acid attenuates STV-induced behavioral, electrophysiological and biochemical alterations by manipulating TRP channel activity in two manners: (1) direct antagonistic action against TRPV1 channels and (2) indirect inhibition of TRP channels by blocking oxidative and inflammatory surge. Therefore, NA can be developed as a potential pharmacotherapeutic adjunct for antiretroviral drug-induced neuropathy.