Diagnosis and therapeutics of neurodegenerative mechanisms is still mysterious field in comparison to other peripheral disease. The exploration of disease mechanisms in patients of neurological disease is immposible due to late diagnosis of disease and scarcity of peripheral biomarkers. In CNS also there are no biomarkers and physicians can only depend on the imaging like techniques for diagnosis. In this view we are exploring the disease mechanisms by using experimental disease models. Our main focus is on Parkinson’s disease and Alzheimer’s disease. We have reported that PD pathology involves the specific role of inducible nitric oxide synthase (NOS) in initiation of dopaminergic neuronal death (Singh et al, 2005). The involvement of mitochondria dependant energy metabolism and intrinsic apoptotic has also been reported during in neuronal death at early phase of disease pathology (Singh et al, 2010). Our both research articles were nationally and internationally cited by number of authors by more than 50 times. We have also reviewed the diversity and expressional regulation of NOS and apoptotic pathways involved in apoptotic death of dopaminergic neurons which are impressively cited by more than 100 authors to date (Kavya et al, 2007; Singh and Dikshit, 2007). Studies have suggested that pesticide rotenone could induce the Parkinson’s like pathology (mainly due to impaired mitochondrial activity) therefore, further my group focused on the investigation of subsequent neurodegenerative mechanisms. We have reported the rotenone and lipopolysacchride induced differential reponses in different rat brain regions. Study showed that the mid brain and striata regions of the rat brain are more vulnerable towards rotenone induced oxidative stress in comparison to other rat brain regions like frontal cortex and hippocampus (Swarnkar et al, 2010). Further we have studied the role of calcium and glia activation in rotenone induced neuronal death. The findings showed that rotenone caused brain region specific activation of astrocytes and microglia and death of neurons (Swarnkar et al, 2013). We have also reported that astrocytes activation is the key step in rotenone induced cytotoxicity and DNA damage (Swarnkar et al, 2012). Involvement of calcium homeostasis has also been reported in roteneon induced neuronal death (Swarnkar et al, 2012). Protein aggregation is also one of the hallmark of most of the neurodegenerative disease which could activate the unfolded protein responses (UPR). UPR involve the increased expression of chaperons and endoplasmic reticulum stress. In this direction we have reported the involvement of endoplasmic reticulam stress in rotenone induced neurotoxicity (Goswami et al, 2014). We have also reviewed the neuropathological responses of astrocytes and microglia under neurodegenerative conditions (Singh et al, 2011). We have reported the involvement of nitric oxide and mitochondria in neurotoxins 6-hydroxydopamine and lipopolysacchride induced DNA damage in astrocytes (Gupta et al, 2015). Further we are evaluating the disease related signaling mechanism involve in neuronal death.
Elucidation of Alzheimers disease pathology is the other focus of lab. We reported that in vitro mouse neuronal N2A cells could be utilized as fast screening test system for new antialzheimer’s therapeutic lead (abstract published in International conference in France, 2015 and MS published in Mol. Neurobiol., 2015). We are further investigating the neurodegenerative mechanisms related to energy metabolism, cellular communication and their correlation with calcium homeostasis and neuronal death.
Besides explorations of neurodegenerative mechanisms we are also investigating the neuroprotective mechanisms. The metabolic enhances piracetam is clinically being used drug at very high doses with no significant adverse effects. However, its mechanism of action is not well known. It has showed the significant protection in ischemia, stroke and epilepsy bot could not be used as independent therapy. To date due to its unknown mechanism of action it could be used as supplement in number of disease. Reports have showed its effect on membrane fluidity and enhancement in mitochondrial activity. We have shown that DNA damage is key step in piracetam induced neuroprotective effects (Goswami et al, 2011). Study in leukocytes and peritoneal macrophage also showed that oxidative DNA damge is key event in piracetam induced cytoprotection (Singh et al, 2011). Further study in astrocytes showed that piracetam induced neuroprotective mechanism involves the caspase independent pathway through prevention in endonuclease G translocation (Gupta et al, 2014).
In addition we are also working on the other antioxidant which could be utilize in neurodegenerative mechanisms. I I have reviewed the promising role of melatonin and antioxidants as neuroprotectant (Joshi et al, 2015; Sarika Singh, 2015).
In collaboration we have reported the improved oral delivery of CDRI’s patented antimalarial drug arteether with complete pharmacokinetic and toxicity profile (Dwevedi et al, 2014). Thymoquinone induced amelioration of iron induced clastogenecity and DNA damage has also been studied by us (Parveen et al, 2014). Polyphenols like (6)-Gingerol induced myeloid leukemia cell death involves reactive oxygen species and activation of miR-27b expression has also been reported (Rastogi et al, 2014).