Potential Neuroprotective Effect of a Neurosteroid in an Experimental Animal Model of Huntington's Disease

Abstract

Huntington's disease is a devastating progressive neurodegenerative disorder with a wide spectrum of motor, cognitive and behavioral abnormalities. HD is characterized by striking regional selectivity of atrophy and neuronal loss. The most prominent atrophy is found in the caudate nucleus and putamen which together comprise the corpus striatum. The cerebral cortex is also affected early in the course of the disease. Severe neuronal loss involves the medium spiny neurons in the caudate and putamen of the striatum of basal ganglia, the pyramidal neurons of the cerebral cortex and to lesser extent, hippocampal and subthalamic neurons. HD is caused by a highly polymorphic CAG trinucleotide repeat expansion in the exon-1 of the gene encoding for Htt protein. This mutation leads to abnormally long polyglutamine (PolyQ) expansion in the Htt protein, which confers one or more toxic functions to muHtt resulting in neurodegeneration. Despite the efforts that have been made to develop new strategies to treat this disorder, there has been no breakthrough and only symptomatic therapies can be helpful but also to a limited extent.

Different animal models have been developed for studying HD, most of which fall into two broad categories, genetic and non-genetic. One of the best choices in modeling HD is 3-NP, a mitochondrial toxin which can effectively induce specific behavioral changes and selective striatal lesions similar to that observed in HD. 3-NP-induced HD phenotype can be manifested in experimental animals as locomotor hypoactivity, disruption of PPI of acoustic startle response, striatal histopathological lesions, reduced oxidative defense, increased inflammation and apoptosis.

The neurosteroid, ADIOL, is a major natural metabolite of the neuroprotective DHEA. In this study, the potential neuroprotective effect of ADIOL against 3-NP-induced neurotoxicity was tested because of its