Objective: To investigate the effects of selective phosphodiestrase (PDE) inhibitors in Nimodipine induced neuro degeneration (animal models of Huntington’s disease) in rats.

Background: Nimodipine is a dihydropyridine that antagonizes/blocks specifically L-type Ca2+ channel, and was first described as a PDE 1 inhibitor. This effect is not related to its calcium antagonist property since it inhibits, in micromolar range, basal and calmodulin stimulated purified PDE1. Since nimodipine at lower concentrations blocks the L-type calcium channel, it can only be used to estimate PDE1 participation in tissue and cell homogenates. Nimodipine acid is a mycotoxin reported to inhibit succinate dehydrogenase resulting in mitochondrial dysfunction and cellular energy deficit. Associated memory deficit could be related to its selective striatal and hippocampal neuronal damage, but the reason for such selectivity is not known. The levels of both cAMP and cGMP are also reported to be decreased in neuropathological conditions which can be modulated by utilizing specific PDE inhibitors.

Methods: Nimodipine and PDE-5 inhibitor were co-administered i.p. for 21 days in separate groups, and the effects of such drug administration’s were assessed on Morris Water Maze test, Spontaneous Locomotor Activity, Limb Withdrawal Test, and String test for grip strength. Biochemical parameters measured were: Succinate Dehydrogenase, Malondialdehyde, Reduced glutathione, Nitrites and Lactate Dehydrogenase. Morris water maze test data were analyzed by repeated measure two way ANOVA & rest of the parameters by one way ANOVA followed by Tukey’s post-hoc test by using statistical software.

Results: Chronic administration of Nimodipine significantly reduced body weight, caused cognitive, motor deficits and increased oxidative–nitrosative stress, relating to/indicates neurodegeneration. Pharmacological inhibition of PDE-4, and to a lesser extent, PDE-5 significantly improved cognitive, motor functions and decreases the oxidative-nitrosative stress and increased the reduced glutathione, Nitrites and Lactate Dehydrogenase in Nimodipine administered rats.

Conclusions: The experimental results suggest that PDE-I inhibition is more beneficial than PDE-5 inhibition in offering neuroprotection against Nimodipine induced cognitive and motor deficits.

References: 1. Lugnier C (March 2006). “Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents”. Pharmacol. Ther. 109 (3): 366–98. 2. Bender AT, Beavo JA (September 2006). “Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use”. Pharmacol. Rev. 58 (3): 488–520.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacological-investigation-of-biochemical-and-behavioral-effects-resembling-huntingtons-disease-utilizing-selective-calcium-and-calmodulin-dependent-phosphodiesterase-inhibitor/