Potential neuroprotective effect of androst‐5‐ene‐3β, 17β‐diol (ADIOL) on the striatum, and substantia nigra in Parkinson's disease rat model

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with behavioral and motor abnormalities. Androst-5-ene-3β, 17β-diol (ADIOL), an estrogen receptor (ER) β agonist, was found to mediate a transrepressive mechanism that selectively modulates the extent of neuroinflammation and, in turn, neurodegeneration. In consensus, ERβ polymorphism was more frequently detected in early-onset PD patients. Thus, in an approach to elucidate the role of ERβ agonists on PD, our study was designed to investigate the possible neuroprotective effect of ADIOL, in three dose levels (0.35, 3.5, 35 mg/kg/day), against rotenone (ROT)-induced PD rat model. Amelioration in striatal dopamine (DA), nuclear factor-kappa B (NF-κB), and the expression of down-stream inflammatory mediators, as well as apoptotic markers were observed in the striatum and substantia nigra (SN) upon pre-treatment with the three doses of ADIOL. Similarly, light microscopy (LM) examination revealed declined degeneration of neurons upon pretreatment with ADIOL. Significant improvement in nigral tyrosine hydroxylase (TH) and reduction of nigral α-synuclein densities were also detected after ADIOL pre-treatment with better results frequently achieved with the middle dose (3.5 mg/kg/day). The middle dose of ADIOL showed behavioral improvement, with elevation in the ATP level, which was emphasized by the improvement in mitochondrial integrity observed upon electron microscopy (EM) examination. In conclusion, the present study confirmed for the first time the ability of ADIOL to protect against neuroinflammation and, in turn, neurodegeneration process and motor dysfunction in PD animal model, which was more obviously observed with the middle dose.

Estrogen receptors and the aging brain

“…Similar effects could not be observed with a selective synthetic ERβ agonist in these studies. However, another study found that the endogenously produced 5-androstene-3β, 17β-diol, an ERβ agonist, protects against neuroinflammation in the rotenone-induced rat model of PD [ 143 ], suggesting that type of PD model and type of selective ER modulators may influence the neuroprotective readouts. Furthermore, a polymorphism in the human ERβ gene was more common in both sexes of early-onset PD patients compared with late-onset patients [ 144 ], whereas ERα polymorphisms appear to not be associated with PD [ 145 ].…”

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

“…As for androstane steroids, DHEA treatment rescued depleted TH-positive neurons and recovered ERK phosphorylation [467]. ADIOL ameliorated rotenone-induced elevation of NF-κB and expression of iNOS and IL-6 [311]. Taken together, these studies suggest a potential protective role of pregnane and androstane steroids in PD pathology, in part, through neuroimmune regulation.…”

“…It serves as a selective modulator of estrogen receptors (ER), effectively suppressing inflammatory reactions in microglia and astrocytes [108]. Studies by Salama et al revealed that ADIOL reduces NF-kB levels in both the striatal and nigral regions of a rat model with rotenone-induced Parkinson's disease (PD) [311]. Additionally, ADIOL promotes the production of the anti-inflammatory cytokines IL-4 and IFN-γ in experimental autoimmune encephalomyelitis, mitigating axonal damage resulting from demyelination by shifting microglial polarization toward a reparative state [312,313].…”

Molecular insights into the potential effects of selective estrogen receptor β agonists in Alzheimer's and Parkinson's diseases

“…Apart from regulating the PD disease-associated PARK genes ERβ could maintain dopamine levels, and reduce neuroinflammation and ROS generation. 131 The knockout of ERβ from the midbrain precursor cells was associated with decreased expression of engrailed homeobox 1 and 2 (EN1 and EN2), and orthodenticle homeobox 2 (OTX2) genes. EN1 and EN2 are essential in the development and maintenance of mesencephalic dopaminergic neurons.…”

“…The mechanisms by which estrogen confers neuroprotective effects in PD are diverse. Apart from regulating the PD disease‐associated PARK genes ERβ could maintain dopamine levels, and reduce neuroinflammation and ROS generation 131 . The knockout of ERβ from the midbrain precursor cells was associated with decreased expression of engrailed homeobox 1 and 2 (EN1 and EN2), and orthodenticle homeobox 2 (OTX2) genes.…”