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Neuroscience & Ageing Biology

Area Co-Ordinators

  • Dr. Aamir Nazir


Neuroscience & Ageing Biology

Summary of drug discovery and development activities

Around 600 NCEs and natural products were submitted for GPCR profiling during last one year and several preliminary hits were identified that are being consolidated. Besides these, several standardized extracts like Tinospora cordifolia were evaluated for cognitive enhancement activities under CSIR’s Phytomission.

Advancing Knowledge frontiers

Controlled release of hydrogen sulfide studied towards significantly reducing ROS stress and increasing dopamine levels in transgenic C. elegans

Hydrogen sulfide, an endogenous signalling molecule, is central to several pathophysiological processes in mammalian systems. It scavenges reactive oxygen species and is known to ameliorate dopaminergic neuronal degeneration in neurotoxin-induced Parkinson's disease models. The rapid volatilization of H2S from spontaneously releasing sulfide salts being a challenge, we describe peptide conjugates which exhibit tris(2-carboxyethyl)phosphine mediated "slow and sustained" H2S release. It is known that H2S is a reducing agent that increases the levels of intracellular glutathione, which in turn decreases the oxidative stress. Such an effect, specifically in dopaminergic neurons, would prevent damage to the dopaminergic system thus augmenting the levels of dopamine. An important hallmark of PD is the inflammatory response; studies employing in vitro systems have reported that monoamine oxidase B (MAO-B), an enzyme primarily responsible for the oxidative degradation of neurotransmitter dopamine, is inhibited by H2S releasing moieties. Hence, in the present study, the observed dopamine enhancing effects could be attributed to the anti-oxidant and anti-inflammatory effects of H2S. The properties of conjugate III in leading to slow and sustained release of H2S probably result in its superior efficacy vis-à-vis countering dopamine decline. In conclusion, a peptide-based system was developed which releases hydrogen sulfide in a controlled manner. These conjugates self-assembled into fibres or spherical structures as a result of self-assembly, and they release hydrogen sulfide at a slower rate compared to ADT-COOH. These conjugates also significantly reduce ROS generated by hydrogen peroxide suggesting their promising antioxidant properties. Interestingly, conjugate III significantly increased the dopamine content, an important neurotransmitter crucial for transporting neuronal signals, which is pivotal for reward-motivated behavior and motor control through dopaminergic signaling (Chem Comm 2019; 55(68): 10142-10145)

Dopamine D1 receptor activation improves adult hippocampal neurogenesis and exerts anxiolytic and antidepressant-like effect in rat model of Parkinson's disease/span>

Parkinson’s disease (PD) is primarily characterized by midbrain dopamine depletion. Dopamine acts through dopamine receptors (D1 to D5) to regulate locomotion, motivation, pleasure, attention, cognitive functions and formation of newborn neurons, all of which are likely to be impaired in PD. Reduced hippocampal neurogenesis associated with dopamine depletion has been demonstrated in patients with PD. However, the precise mechanism to regulate multiple steps of adult hippocampal neurogenesis by dopamine receptor(s) is still unknown. This study tested whether pharmacological agonism and antagonism of dopamine D1 and D2 receptor regulate nonmotor symptoms, neural stem cell (NSC) proliferation and fate specification and explored the cellular mechanism(s) underlying dopamine receptor (D1 and D2)- mediated adult hippocampal neurogenesis in rat model of PD-like phenotypes. It was found that single unilateral intra-medial forebrain bundle administration of 6-hydroxydopamine (6-OHDA) reduced D1 receptor level in the hippocampus. Pharmacological agonism of D1 receptor exerts anxiolytic and antidepressant-like effects as well as enhanced NSC proliferation, long-term survival and neuronal differentiation by positively regulating Wnt/β-catenin signaling pathway in hippocampus in PD rats. shRNA lentivirus mediated knockdown of Axin-2, a negative regulator of Wnt/β-catenin signaling potentially attenuated D1 receptor antagonist induced anxiety and depression-like phenotypes and impairment in adult hippocampal neurogenesis in PD rats. These results suggest that improved nonmotor symptoms and hippocampal neurogenesis in PD rats is controlled by D1-like receptors and involve the activation of Wnt/β-catenin signaling (Neurochem Int. 2019; Jan; 122:170-186).

Novel Tetrahydroquinazolinamines as selective Histamine 3 receptor antagonists for the treatment of obesity

The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. In this study, synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50 < 0.04 μM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.