1. Drug Discovery
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Complete battery of behavioral test is performed in our lab as a part of Essential Safety Pharmacology CNS studies of a test compound, including Animal activity monitoring by Optovarimax system, Motor coordination by Rotarod, Body temperature, Anaelgesia activity by Hot Plate and Gross behavior assessment.
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A battery of behavioral assays like forced swim test, tail suspension test, light and dark test, elevated plus maze, open field activity , Morris water maze test, Grip Strength, Social interaction and rotarod test are being used as screening models for depression, anxiety, stress, dementia and Parkinson’s disease.
➤ Repositioning of bioactives for new leadsOpen Source programs
2. Basic Research
Understanding neurogenesis during neurodegenerative disorders
Evidence of adult neurogenesis has resulted in new possibility of treatment in neurodegenerative disease. Neural precursor cells resides majorly in two neurogenic region; subventricular zone (SVZ) lining lateral ventricle & subgranular zone (SGZ) part of the hippocampal dentate gyrus (DG) and recently also reported in nonneurogenic striatum, substantia nigra (SN) and hypothalamus. These neurogenic regions have potential to replenish the extensive loss of neurons that exist in neurodegenerative disorder. Parkinson’s disease (PD) is a result of degeneration of dopaminergic neurons of nigrostraital pathway that has been found proximally to SVZ resulting in cognitive and motor impairments. There is strong evidence supporting that neurogenesis is compromised in PD, which has been related to the nonmotor symptoms of the disease. Further it has been found that impaired neurogenesis is partially a result of loss of dopamine in neurogenic region. Thus, restoring the dopaminergic pathway in PD patients may have implications not only for motor function improvement, but for other cognitive and autonomic symptoms. Currently, there are no effective treatments that can prevent or reverses the neurodegeneration process in the brain. Thus defining a therapy to stimulate adult neurogenesis in these neurogenic and non-neurogenic niches by means of drugs, trophic factors, exercise or cell therapy may be helpful in retrieval of neuronal loss.
Currently, we have three well-known rodent model of PDs disease – (MPTP) induced mice model, 6-hydroxydopamine (6-OHDA) induced rat model
and rotenone induced rat model. MPTP model involves systemic injection of toxin MPTP which metabolize to MPP+ that result in nerve terminal loss
and degeneration within 7-9 days. MPP+ is carried by dopamine transporter (DAT) where it blocks mitochondrial activity. 6-OHDA is a neurotoxic
product formed by the auto-oxidation of endogenous dopamine and closely mimics the pathophysiology of PD. 6-OHDA cannot cross the blood brain barrier
thus it directly injected into the brain through stereotaxic surgery. Unilaterally injection of 6-OHDA in the medial forebrain bundle (MFB) region
results in retrograde degeneration of dopaminergic neurons in the SNpc. Degree of degeneration is confirmed by rotational behavior which include
amphetamine induced ipsilateral rotation. Rotenone is highly lipophilic neurotoxin which crosses the BBB and block complex I activity of mitochondria
resulting in excessive ROS thereby causing the death of dopaminergic neurons. Exposure of rotenone to rats induced selective complex I inhibition
mediated death of dopaminergic neurons, hence this model is very useful to study the mitochondrial dysfunctioning in PD.
Understanding the pathophysiology of Psychosis
Our group has also focused on neurological disorders such as psychosis, depression and anxiety.
Attempts have been made to attribute PCP- and ketamine-induced psychosis to a wide variety of targets including dopaminergic, monoaminergic,
cholinergic, GABAergic, opiatergic, sigma), and, most recently, to high D2 receptors. However, the behavioral effects of NMDAR antagonists that
are relevant to schizophrenia persist in the absence of dopamine activity or dopamine antagonists. Both the absolute concentrations and the
rank-order potency with which a range of compounds induce psychotomimetic effects in humans and animal models conforms to their rank order of
potency at NMDAR but not other receptor types. To date, all compounds that bind to the PCP site of the NMDAR have been found to induce psychosis
when given to humans, whereas the same is not true for proposed alternative non-NMDAR-related targets, so that NMDAR blockade by these agents
appears both necessary and sufficient to explain their psychotomimetic effects. Moreover, the effects do not appear to be unique to agents that
inhibit NMDAR via the PCP site. Therefore, our group has used N-methyl D-aspartate receptor antagonist to mimic a state of clinical psychosis in
mice to explore the pathology of disease. Further, depression has been associated with various cardiovascular risk factors such as hypertension,
obesity, atherogenic dyslipidemia and hyperglycemia.
Understanding the role of HPA axis in metabolic syndrome
In depressive disorder, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and changes in the immune system is more pronounced. On the other hand, somatic diseases such as obesity, hyperlipidemia, hypertension and diabetes mellitus type 2 are now perceived as important comorbid conditions in patients with depression. Hence, our group is also interested in the establishing a link between hyperactivity of the HPA axis and metabolic dysfunction in rodents.