Central Drug Research Institute

About: Central Drug Research Institute is a facility organization based out in Lucknow, Uttar Pradesh, India. It is known for research contribution in the topics: Catalysis & Leishmania donovani. The organization has 4357 authors who have published 7257 publications receiving 143871 citations. The organization is also known as: Central Drug Research Institute, Lucknow & CDRI.

Mitochondrial dysfunction: A crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain

Abstract: Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction.

Core engagement with β-arrestin is dispensable for agonist-induced vasopressin receptor endocytosis and ERK activation

Abstract: G protein-coupled receptors (GPCRs) exhibit highly conserved activation and signaling mechanisms by which agonist stimulation leads to coupling of heterotrimeric G proteins and generation of second messenger response. This is followed by receptor phosphorylation, primarily in the carboxyl terminus but also in the cytoplasmic loops, and subsequent binding of arrestins. GPCRs typically recruit arrestins through two different sets of interactions, one involving phosphorylated receptor tail and the other mediated by the receptor core. The engagement of both set of interactions (tail and core) is generally believed to be necessary for arrestin-dependent functional outcomes such as receptor desensitization, endocytosis, and G protein-independent signaling. Here we demonstrate that a vasopressin receptor (V2R) mutant with truncated third intracellular loop (V2RΔICL3) can interact with β-arrestin 1 (βarr1) only through the phosphorylated tail without engaging the core interaction. Of interest, such a partially engaged V2RΔICL3-βarr1 complex can efficiently interact with clathrin terminal domain and ERK2 MAPK in vitro. Furthermore, this core interaction-deficient V2R mutant exhibits efficient endocytosis and ERK activation upon agonist stimulation. Our data suggest that core interaction with βarr is dispensable for V2R endocytosis and ERK activation and therefore provide novel insights into refining the current understanding of functional requirements in biphasic GPCR-βarr interaction.