Currently, about 50% of depressed patient do not respond to available therapeutics from all classes, suggesting huge unmet medical need. One of our goal is to understand the molecular mechanisms of treatment resistant depression (TRD) and molecular determinant of antidepressant response. To achieve this, we first developed a rodent model of TRD (Dogra S, et al. 2016), and currently we are investigating the expression patterns of various molecular correlates (e.g., BDNF) in different brain circuits, epigenetic modulation glutamatergic & serotonergic neurotransmission, and architectural plasticity (e.g., spine density, neuronal arborization) in rodent models of depression. Furthermore, we are also investigating the role of HA neurotransmission as well as Omega-3 Fatty acids action through GPR40 in brain for the modulation of affect. • Dogra S, ……, Yadav PN. Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression. Sci Rep. 2016; 6:33401. • Kumar A, ….., Yadav PN. Chronic histamine 3 receptor antagonism alleviates depression like conditions in mice via modulation of brain-derived neurotrophic factor and hypothalamus-pituitary adrenal axis. Psychoneuroendocrinology. 2019; 101: 128-137. • Sona C, …, Yadav PN. Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice. Neurobiol Dis. 2018; 118: 94-107
Neuropathic pain is an extremely common condition and various estimates of the prevalence range from a low of about 3% to a high of over 12%, with most estimates settling at around 10% (WHO data). That number is likely to grow as the population ages and the prevalence of type 2 diabetes increases. Coupling those numbers with a difficult to treat disease makes it an important and growing health issue. Neuropathic pain is often not treated well due to lack of both effectiveness and tolerability of currently available drugs. Therefore, we are approaching this hugely unmet clinical need by two following methods: • Since clear understanding of etiology/pathophysiology of neuropathic pain is still lacking, a NMR based metabolomics as well as epigenetic profiling using Chip-Seq being performed to gain further insight in various pathways/circuitries involved in this disease, which can be harnessed to develop novel therapeutics. • We have successfully discovered a series of novel and extremely biased Kappa opioid receptor agonist, which is highly efficacious in SNL model of neuropathic pain and currently being developed for the treatment of neuropathic pain (patent has been filed).
The build-up of misfolded and toxic protein aggregates is associated with multiple CNS diseases. Efficient protein quality control machinery is required to maintain homeostasis and good health. One of our aim is to fundamental mechanisms of unwanted protein aggregates formation in CNS that impairs communication among brain cells as wells optimal functioning various neurocircuits involved in cognition and affect. The larger aim being identification of protein targets, epigenetic interventions and functional processes, that can aid in efficient clearance of noxious build-ups while eliciting positive effects on other key factors including neuroprotection, neuronal repair and functional outcome related to age associated neurodegenerative diseases. • One of our approach is to use of humanized C. elegance system for genetic and pharmacological interventions, including RNAi induced gene silencing, transgene constructs (GFP/YFP), Transcriptome analysis, micro RNA expression studies and associated aspects related to protein aggregation, cellular signaling and neuronal cell death, towards understanding mechanistic aspects related to human Alzheimer’s and Parkinson’s disease (Haw R, et al. 2020): • Evidence of adult neurogenesis has resulted in new possibility of treatment in neurodegenerative disease. Neural precursor cells reside majorly in two neurogenic regions; subventricular zone (SVZ) lining lateral ventricle & subgranular zone (SGZ) part of the hippocampal dentate gyrus (DG). Some recent reports have also provide evidence of neurogenesis in non-neurogenic brain areas including, striatum, substantia nigra (SN) and hypothalamus. These neurogenic regions have potential to replenish the extensive loss of neurons that occur in neurodegenerative disorder (Singh S, et al, 2018). With this background, we are using pharmacological and genetic approaches to test the hypothesis “the loss of neurons can be compensated by region specific increase in adult neurogenesis”. • One of our approaches is to discover novel and specific KAT activator Neurodegenerative Diseases. The major emphasis has been given to the possible utilization of their recently discovered carbon nanospheres. The mechanism of its ability to cross the blood-brain barrier, delivery of the HAT activator molecule in the mammalian brain. We have successfully conjugated a histone acetyltransferase activator with the CSP and could target it to mice brain. The conjugated molecule could induce histone hyperacetylation in hippocampus of mice brain thereby inducing neurogenesis and long term spatial memory formation. Recently we have shown that indeed the specific activation of p300/CBP could result in almost complete recovery of memory in the neurodegenerative disease model. This activation could also dramatically lead to repairing of spinal injury in mice and rat (Chatterjee S, et al, 2018). References: • Haque R, ……, Nazir A* (2020; in press) Human insulin modulates a-synuclein aggregation via DAF-2/DAF-16 signalling pathway by antagonising DAF-2 receptor in C. elegans model of Parkinson’s disease. Oncotarget. 2020 Feb 11; 11(5). • Singh S, …., Shukla S. Axin-2 Knockdown Promote Mitochondrial Biogenesis and Dopaminergic neurogenesis by regulating Wnt/ß-catenin Signaling in Rat Model of Parkinsons disease. Free Radic Biol Med. 2018 Aug 31; 129:73-87. • Chatterjee S, ……, Kundu TK*, Boutillier AL*. (2018). Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med: 10(11):e8587.
• We employ following 3 types of live cells functional assays, which measures G-protein coupled receptor (GPCR) dependent formation of secondary messengers (cAMP using GloSensor, Ca++ flux using gCAMP6b biosensor) or ß-arrestin recruitment to GPCRs to discover selective agonist and antagonists of target GPCRs. We are focused to discover novel and high affinity ligands (agonists, Antagonists, PAM) for 9 GPCRs (KOR, HTR2C, HTR6, HRH3, CXCR3, CXCR4, TGR5, DRD1, DRD5), which can be developed for the treatment of various CVS and CNS disorders. • We have rodent neurobehavioral facility to conduct battery of behavioral assays like forced swim test, tail suspension test, light and dark test, elevated plus maze, open field locomoter activity, Morris water maze test, Grip Strength, Social interaction and rotarod tests, which are being used for depression, anxiety, stress, cognitive impairments and Parkinson’s disease. • We also have extensive battery of physiological and behavioral assay system to measure nociception (pain), such as Digital/electronic Von Frey system and Hargreaves system to measure Allodynia and hyperalgesia, hot plate test system to measure planter nociception. • Humanized transgenic fluorescent C. elegance system to conduct systematic screening/profiling of test compounds for life-span studies and neurodegenerative disorders (AD &PD) • MPTP and 6-OHDA induced Rat models for studies of Parkinson’s disease • GLP accredited lab for essential CNS safety pharmacology studies of a test compound as per Schedule “Y”, including animal activity monitoring by Optovarimax system, motor coordination by Rotarod, core body temperature, Analgesia activity by Hot Plate and gross behavior assessment.
Patents: • 0046NF2017 (India): Substituted Methanopyrido [2, 1-a] Isoindolones As MACHR modulators for treating various associated pathophysiological conditions. Application Number: 201711017657 , Prov. Date: 19/05/2017. • PCT/IN2018/050317: Substituted METHANOPYRIDO[2, 1-a]ISOINDOLONES as mAChR Modulators for Treating Various Associated Pathophysiological Conditions and Process For Preparation Thereof. • 0242NF2015 (India): Eutectic formulation of migrainolytic for rapid nose to brain transport; Inventors: Rajeev Ranjan, Prem Narayan Yadav, Tabassum Khan; Application no.201611003053b • 0266NF2015 (India): Pyranone fused aza-heterocyclic fluorescent dyes as a neuron selective fluorescent probe.
Dr. PREM NARAYAN YADAV
Principal Scientist
CSIR-CDRI
Dr. SHUBHA SHUKLA
Senior Scientist
Dr. Sonia Verma
Scientist
Dr. Aravind singh kshatri
Dr. AAMIR NAZIR
Senior Principal Scientist
Dr. SARIKA SINGH
Dr. DURGA PRASAD MISHRA