COMPARATIVE EFFECT OF PHOSPHODIESTERASE INHIBITORS ON INTRACEREBROVENTRICULAR COLCHICINE MODEL OF MEMORY IMPAIRMENTS IN RATS

Sidharth Mehan; Vijay Singh Nain; Harikesh Meena; Deepak Sharma; Manjit Singh

Sidharth Mehan Department of Pharmacology G D college of pharmacy, Jodhpur, India.
Vijay Singh Nain Department of Pharmacology G D college of pharmacy, Jodhpur, India.
Harikesh Meena Department of Pharmacology GD Memorial college of Pharmacy, Jodhpur, India
Deepak Sharma Department of Pharmacology GD Memorial college of Pharmacy, Jodhpur, India
Manjit Singh Department of Pharmacology GD Memorial college of Pharmacy, Jodhpur, India

Keywords: Alzherimer’s diseases; Intracerebroventricular; Rat; PDE

Abstract

Alzheimer’s disease (AD) is a progressive, age related neurodegenerative disease, characterized by a progressive decline in memory, cognitive performance and loss of acquired skills leading to apraxia, agnosia and aphasia. Central colchicine induced cognitive dysfunction and oxidative stress in rats closely resembles with the characteristic features of Alzheimer’s type of dementia. The present study was designed to investigate the comparative effect of vinpocetine (PDE1 inhibitor) and Ro 20-1724 (PDE4inhibitor) on intracerebroventricular (ICV) colchcine induced experimental sporadic dementia of Alzheimer's type. Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. Infusion of colchicine impaired learning and memory, increased oxidative– nitritive stress and induced cholinergic hypofunction in rats. Treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) and Ro 20-1724 (0.5, 1 and 2 /kg i.p.) for 21 days following first ICV colchicines administration significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Furthermore, both PDE 1 and 4 inhibitors significantly reduced the oxidative–nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. The possible mechanism of said effects of the compounds investigated may be due to their PDE inhibitory activity resulting in enhanced levels of second messengers which may be consisting to the antioxidant and anti-inflammatory action, and modulation of cholinergic activity and prevention of cell damage collectively leading to cognitive enhancement.