Investigations on 16-Arylideno Steroids as a New Class of Neuroprotective Agents for the Treatment of Alzheimer's and Parkinson's Diseases.

Abstract

Neuroinflammatory mechanisms mediated by activated glial and cytokines (TNF-α, IL-1β) might contribute to neuronal degeneration leading to Alzheimer's (AD) and Parkinson's disease (PD). Lipopolysaccharide (LPS) is an inflammogen derived from the cell wall of Gram-negative bacteria, which promotes neuroinflammation and subsequent neurodegeneration. Dehydroepiandrosterone (DHEA) and testosterone have been reported as neuroprotective steroids useful for the treatment of various neurodegenerative disorders. In the present study, several 16-arylidene steroidal derivatives have been evaluated as neuroprotective agents in LPS-treated animal models. It was observed that 16-arylidene steroidal derivatives 1a-d and 6a-h considerably improve LPS-induced learning, memory, and movement deficits in animal models. Biochemical estimations of brain serum of treated animals revealed suppression of oxidative and nitrosative stress, acetylcholinesterase activity, and reduction in TNF-α levels, which were induced through LPS mediated neuroinflammatory mechanisms leading to neurodegeneration of brain. Of all the steroidal derivatives, 16-(4-pyridylidene) steroid 1c and its 4-aza analogue 6c were found to be the most active neuroprotective agents and produced effects comparable to standard drug celecoxib at a much lower dose and better than dexamethasone at the same dose in terms of behavioral, biochemical, and molecular aspects.