quotAmelioration of 6 0HDA and MPTP induced parkinsonism using nanoparticles of Hrantagonist and c Jun N terminal kinase JNK inhibitorquot

Abstract

quotObjective: The design of our hypothesis includes the development of H3 antagonist Conessine, and JNK-3 inhibitor 1,9-Pyrazoloanthrone (1,9-P) loaded liposomal drug delivery system and the evaluation of its neuroprotective efficiency in-silico, in-vitro and in vivo. newlineMethodology: Followed by in silico and in vitro screening the H3 antagonist conessine and JNK-3 inhibitor 1,9-P were selected for preparation of liposomes to cross BBB effectively. The extent of neuroprotective effect of formulation were evaluated by molecular expression of anti-apoptotic and apoptotic proteins and Mitochondrial complex-I activity in cell line. The 6-OHDA and MPTP induced Parkinson models were used for study and accordingly groups were made. The histopathology and iron degeneration in brain and various behavioral parameters were also estimated using appropriate methods. newlineResults: The preliminary in silico and enzyme kinetic study showed good potency of Conessine and 1,9-P over H3 receptor and JNK-3 respectively. The AO/EB and Hoechst 33342 staining assay showed effectively reduction in apoptosis in treatment groups. The in vitro study showed significant reduction in apoptotic proteins and increased Bcl-2 an ant-apoptotic protein level. The biodistribution studies showed effective uptake of liposomes in brain than plain drug solution and better pharmacokinetic activity. The in vivo evaluation and striatal dopamine estimation further justify the neuroprotective dopaminergic system restoring activity of selected molecules. The histopathology and ion degeneration studies showed protection of dopaminergic neurons in treatment group from neurotoxic chemicals. newlineConclusion: The present study tried to identify a non-dopaminergic pathway for the treatment of Parkinson s disease by altering the causative molecular pathway with minimal side effects. The current drug therapy can lay a new path to treat the Parkinson s disease by targeting alternative pathway than dopaminergic system. newlinequot