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.

The Use of Switchable Polarity Solvents for the Synthesis of 16‐Arylidene Steroids via Claisen–Schmidt Condensation

“…Benzylidene derivatives obtained by the Claisen–Schmidt condensation of steroidal ketones may serve as starting materials for the synthesis of compounds of pharmacological importance or may show favourable biological activity themselves . The 16‐arylidene group was found to be a good pharmacophore for cytotoxic activity.…”

Crystal and Molecular Structure and DFT Calculations of the Steroidal Oxime 6E-Hydroximino-androst-4-ene-3,17-dione (C19H25NO3) a Molecule with Antiproliferative Activity

“…In another area of therapeutic interest, two recent studies involving biomedical-steroid function, promise to lead to interesting structure function studies. It was shown that 16,17-pyrazoline substituted heterosteroids [21] and 16-arylideno steroids [22] both represent a new class of neuroprotective agents for the treatment of Alzheimer's and Parkinson's diseases. In particular it was shown that the introduction of a pyrazoline ring at the 16,17 position of the steroid skeleton resulted in improvement of neuroprotective effects.…”

Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review

“…Recently Singh and Bansal reported the neuroprotective effects of 16 ‐ pyridylidene steroids and their 4‐aza analogues in LPS (lipopolysaccharides)‐treated animal models . It was observed that the 16 ‐ arylidene steroidal derivatives significantly improve LPS‐induced learning, memory, and movement deficits in animal models.…”

“…Synthetic modifica- Recently Singh and Bansal reported the neuroprotective effects of 16-pyridylidene steroids and their 4-aza analogues in LPS (lipopolysaccharides)-treated animal models. 190 It was observed that the 16-arylidene steroidal derivatives significantly improve LPS-induced learning, memory, and movement deficits in animal models. In addition, the results of biochemical estimations of brain serum of treated animals have shown the suppression of oxidative and nitrosative stress, AChE activity, and reduction in TNF-levels, which were induced through LPS-mediated neuroinflammatory mechanisms.…”

“…6) were found to be the most active neuroprotective agents and produced effects comparable to standard drugs celecoxib and dexamethasone in terms of behavioral, biochemical, and molecular aspects. 190 DHEA analogues with spiro-epoxy modifications at C-3 or C-17 positions produce significant antiapoptotic and neuroprotective effects.…”