الفهرس 
Literature ReviewOnly 14 pages are availabe for public view
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Abstract
A constellation of events are implicated in the pathogenesis of Parkinson’s disease (PD). However, there is a growing evidence that neuroinflammation is closely linked to dopaminergic cell death and that agents capable of reducing the expression of inflammatory mediators may alleviate the neurodegeneration process in PD. Simultaneously, androst- 5-ene-3β, 17β-diol (ADIOL), an estrogen receptor (ER) β agonist, was found to mediate a transrepressive mechanism, where the ADIOL-ERβ-C-terminal binding protein (CtBP) repression pathway could selectively modulate the extent and duration of neuroinflammation. In an attempt to examine this pathway in PD, the current study was designed to investigate the possible neuroprotective effect of 3 different doses of ADIOL against a rotenone-induced PD rat model. This was carried out by treating rats with subcutaneous (s.c.) dose of ADIOL (0.35, 3.5 and 35 mg/kg/day) one hour earlier to intraperitoneal (i.p.) injection of rotenone (1.5 mg/kg/day) for 30 days. One day after the last injections, the animals were tested for changes in catalepsy, postural instability and locomotor behavior. Rats were then divided into 3 subsets for assessment of neurochemical parameters, histopathological and electron microscopy (EM) examination. Unlike the other 2 doses, the middle dose of ADIOL (3.5 mg/kg/day) showed declined descent latency upon performing bar test and elevation in the number of squares crossed in the open field test, with elevation in the ATP level in both of the striatum and substantia nigra (SN), which was emphasized by the improvement in mitochondrial integrity observed upon EM examination. Amelioration in the striatal dopamine (DA), nuclear factor-kappa B (NF-κB) levels and the expression of the downstream inflammatory mediators; inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6) and B-cell activating factor (BAFF), as well as the anti-apoptotic marker; B-cell lymphoma 2 (Bcl-2) with decline in the pro-apoptotic markers; caspase-3 and Bcl2-associated X protein (Bax) was observed in both the striatum and SN upon administration of the 3 doses of ADIOL. Similarly, light microscopy (LM) examination revealed improvement in the number of viable neurons in both the striatum and SN pars compacta (SNpc), and nigral tyrosine hydroxylase (TH) immunoreactivity, with decline in the nigral α-synuclein density following treatment with the 3 doses of ADIOL, with even better results frequently achieved with the middle dose. On the other side, the high ADIOL dose was only capable to produce further reduction in striatal NF-κB than the low dose, and more decline in the nigral expression of iNOS and BAFF than both the low and middle doses. In conclusion, the present study confirmed for the first time the ability of ADIOL to alleviate neuroinflammation and, in turn, neurodegeneration process and motor dysfunction in PD, which was more obviously observed with the middle dose.
Keywords: Parkinson’s disease, neurodegeneration, striatum, substantia nigra, rotenone,
neuroinflammation, androst-5-ene-3β, 17β-diol, estrogen receptor