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  • memantine hydrochloride Among the different factors that mod


    Among the different factors that modulate Schwann cell biology, several studies pointed out the role played by neuroactive steroids, in particular progesterone (P4) and its derivatives dihydroprogesterone (DHP) and allopregnanolone (ALLO). Schwann memantine hydrochloride are steroidogenic, possessing the entire enzymatic machinery required for neuroactive steroid synthesis [7], [8], [9], [10], [11]. Progestogens control different aspects of Schwann cell biology and pathophysiology, both through classical genomic and non-genomic mechanisms. ALLO, which allosterically modulates the GABA-A receptor [12], is responsible for most of the effects reported in the literature, being responsible for the regulation of cell proliferation [13], peripheral myelin protein of 22KDa (PMP22) expression [14], GABA synthesis [15], GABA-B receptor expression levels [16], and glutamate trafficking [13]. Other effects are mediated by P4- or DHP-mediated nuclear progesterone receptor (PR) activation, for example, the modulation of myelin protein zero (P0) expression [14]. It is important to note that progestogens have also been reported to exert positive effects in Schwann cells in sciatic nerves after aging [17], cryolesion [18], transection [19], and crush injury [20]. Not all progestogens’ actions in Schwann cells can be fully explained by the activation of PR and GABA-A. A novel class of membrane progesterone receptors (mPRs) may be potentially involved in modulating Schwann cell physiology. mPRs are a group of progestogen binding receptors localized on the cell membrane, belonging to the progestin and adipoQ receptor (PAQR) family [21], [22]. Five mPRs have been identified: mPRα, mPRβ, mPRγ, mPRδ and mPRε [23], [24], [25]. They are metabotropic receptors with seven trans-membrane domains, coupled to G proteins. mPRα, β and γ seem to be coupled to an inhibitory Gi/o protein [21], [23], [24], while mPRδ and ε are coupled with stimulatory Gs proteins [25]. Studies by various research groups have demonstrated that mPRs are present in different areas of the CNS, being widely expressed both in the encephalon and in the spinal cord [24], [25], [26], [27], [28], [29], [30]. Several lines of evidence suggest that mPRs may be involved in the modulation of progestogens’ neuroprotective actions in the nervous system. For example, a study conducted using the GT1-7 neuronal cell line model, which express mPRα and β [31] and a very low level of mPRδ, has shown that both P4 and ALLO at 20 and 100nM concentrations significantly reduced apoptosis and cell death in response to serum-starvation in an in vitro assay [32]. A similar effect was observed in mPRδ-transfected cells and in a hippocampal cell line, suggesting that mPRδ could contribute to this anti-apoptotic effect [25]. Under normal physiological conditions mPRs are not expressed by glial cells in the brain [29], and only mPRα is expressed by oligodendrocytes and astrocytes in the spinal cord [26]. However, it was also reported that mPRα expression is induced after traumatic brain injury in oligodendrocytes, astrocytes and microglia, both in the lesion core and peri-lesioned area, suggesting it may have a role in glia-mediated neuroprotective actions of P4 [29]. Another protein that can be involved is progesterone receptor membrane component 1 (PGRMC1). PGRMC1 does not bind P4, and was reported to function as an adaptor protein, mediating mPRα translocation to the cell membrane, leading to the formation of a membrane progesterone receptor complex formed by PGRMC1 and mPRα, with the latter being responsible for P4 binding and intracellular signaling [33]. In this paper, we investigated the hypothesis that mPRs are present and active in Schwann cells, and that they may have a role in the modulation of Schwann cell pathophysiology. To perform these studies, we used the progestogens P4, Org-OD-02-0 (02), and promegestone (R5020). These compounds represent a reliable pharmacological tool to discriminate among mPR- and PR-mediated effects. The specific mPR agonist 02 binds human mPRα with higher affinity than P4, whereas 02 has lower binding affinity for PR and displays no PR agonist activity [34]. On the other hand, R5020 is a high affinity specific PR agonist, having low affinity for mPRs [21].