Browsing by Author "Sumedha Mukherjee"

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Identification of potential inhibitors of PARP-1, a regulator of caspase-independent cell death pathway, from Withania somnifera phytochemicals for combating neurotoxicity: A structure-based in-silico study
(World Scientific Publishing Co. Pte Ltd, 2017) Sumedha Mukherjee; Gaurav Kumar; Ranjana Patnaik
Poly (ADP-ribose) polymerase-1 (PARP-1) reverses DNA damage by repairing DNA nicks and breaks in the normal cellular environment. However, during abnormal conditions like stroke and other neurological disorders, overactivation of PARP-1 leads to neuronal cell death via a caspase-independent programmed cell death pathway. Strategies involving inhibition or knockout of PARP-1 have proved beneficial in combating neuro-cytotoxicity. In this study, we performed in-silico analysis of 27 phytochemicals of Withania somnifera (Ashwagandha), to investigate their inhibition efficiency against PARP-1. Out of 27 phytochemicals, we report 12 phytochemicals binding to the catalytic domain of PARP-1 with an affinity higher than FR257517, PJ34 and Talazoparib (highly potent inhibitors of the enzyme). Among these 12 compounds, five phytochemicals namely Stigmasterol, Withacnistin, Withaferin A, Withanolide G and Withanolide B show an exceptionally high binding affinity for the catalytic domain of PARP-1 and bind to the enzyme with similar hydrogen bond formation and hydrophobic interaction pattern as their inhibitors. All of these phytochemicals are BBB permeable so that they can be further developed into potential future neuro-Therapeutic drugs against neurodegenerative disorders involving neuronal cell death. © 2017 World Scientific Publishing Company.
Neuroprotective effect of chlorogenic acid in global cerebral ischemia-reperfusion rat model
(Springer Verlag, 2019) Gaurav Kumar; Sumedha Mukherjee; Pankaj Paliwal; Saumitra Sen Singh; Hareram Birla; Surya Pratap Singh; Sairam Krishnamurthy; Ranjana Patnaik
The ischemic cascade is initiated in the hypoperfused region of the brain that leads to neuronal cell death. Identification of multi-target inhibitor against prominent molecular mediators of ischemic cascade might be a suitable strategy to combat cerebral ischemic stroke. The present study is designed to evaluate the neuroprotective efficacy of chlorogenic acid (CGA) in the global cerebral ischemic rat model. The effective dose of CGA was evaluated on the basis of reduction in cerebral infarction area percentage, Evans blue extravasation, and restoration of brain water content. The expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and caspase-3 was evaluated by immunohistochemistry and morphological and cellular alterations in the cortex were observed by brain histology. The level of glutamate, calcium, and nitrate in different regions of the brain, as well as cerebrospinal fluid (CSF), was evaluated. The level of calcium and nitrate was compared with ifenprodil—an antagonist of N-methyl-D-aspartate receptor (NMDAR) and 7-nitroindazole—an inhibitor of neuronal nitric oxide synthase (nNOS) respectively. Further, molecular docking was performed to compare the inhibition potential of CGA against NMDAR and nNOS with their inhibitors. Dose optimization results revealed that intranasal administration of CGA (10 mg/kg b.w.) significantly reduced the cerebral infarction area, Evans blue extravasation and restored the brain water content compared with ischemia group. It also significantly reduced the calcium, nitrate, and glutamate levels compared with ischemia group in the cortex, hippocampus cerebellum, and CSF. Immunohistochemical analysis revealed that CGA significantly reduced the expression of TNF-α, iNOS, and caspase-3 as compared with the ischemia group. In molecular docking study, CGA displayed similar binding interaction as that of Ifenprodil and 7-nitroindazole with NMDAR and nNOS respectively. The current findings suggest that the treatment with CGA confers neuroprotection in global ischemic insult by inhibiting and downregulating the different molecular markers of cerebral ischemia. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Pharmacokinetics and brain penetration study of chlorogenic acid in rats
(Taylor and Francis Ltd, 2019) Gaurav Kumar; Pankaj Paliwal; Sumedha Mukherjee; Nishant Patnaik; Sairam Krishnamurthy; Ranjana Patnaik
1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles–Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path. 2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10 mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method. 3. The study observes that CGA is rapidly absorbed in plasma with t max of 1 min similar to IV route after IN administration. The peak plasma concentration and AUC 0–24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route. 4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360 min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUC brain, IN ) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUC brain, IV ) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.