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Gene & Protein in Disease GPER1 in brain and heart diseases

to reduced neuroinflammation and cerebral Aβ deposition in the risk of developing PD. 90,91 Nevertheless, the
as well as alleviated cognitive impairment in female AD beneficial effect of estrogen has been well-described
mice. Regarding GPER1, the study showed that the anti- in both in vitro and in vivo models, 92-94 leading to the
inflammatory effect of SDG was mediated by GPER1 assumption of sex-specific differences in PD development
signaling and could be abolished by its antagonist G-15. and therapy. The major challenges in understanding
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Equivalently, there is evidence that genistein (GEN), sex-specific differences in PD development include the
another phytoestrogen extracted from leguminous plants, identification of new pathways and correlation of sex
inhibits lipopolysaccharide (LPS)-induced inflammation with heterogeneous clinical outcomes. Reekes et al.
in microglia by reducing the production of inducible indicated that men are more cognitively impaired than
nitric oxide synthase (iNOS), tumor necrosis factor women, revealing that sex is more strongly associated
(TNF), IL-1β, and IL-6, which is dependent on GPER1 with cognitive performance than motor phenotype.
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because G-15 treatment abolished the beneficial effects In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
of GEN. Another phytoestrogen, s-equol, a bacterial (MPTP)-induced animal model of parkinsonism, adult
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metabolite of the soy isoflavone daidzein, improved male C57BL/6 mice exhibited an increase in the number
cerebellar development in vitro by influencing astrocytes of tyrosine hydroxylase-immunoreactive cells, reduced
and neurons while mediating GPER1 signaling. activation of microglia, and decreased production of
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Subsequently, it was confirmed that the isoflavone GEN, proinflammatory cytokines after 12 days of treatment
daidzein, and s-equol affect dendrite arborization and with the GPER1 agonist G-1. The anti-inflammatory
total number of Purkinje cells through GPER1 and ERα effect of G-1 was abolished by the treatment of wild-type
in murine primary cerebellar cultures. In particular, the (WT) mice with the GPER1 antagonist G-15. Further
effect of s-equol on neurite outgrowth was shown to be in vitro studies demonstrated that GPER1 activation
mediated by GPER1, as GPER1 knockdown (KD) or G-15 reduced the release of proinflammatory cytokines from
treatment reduced the beneficial effects. Consistent with BV2 microglial cells after MPTP stimulation, indicating
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this, s-equol diminished the LPS-induced production of that GPER1 mediates the anti-neuroinflammatory effect
NO and iNOS in astrocytes, which was partially induced of estrogen in experimental PD progression. Treatment
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by GPER1 because G-15 treatment attenuated the anti- with G-1 exerted similar effects as those observed after
inflammatory effect. Regarding daidzein, a previous study treatment with E2, resulting in increased concentration
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on primary murine cerebellar cultures showed inhibition and turnover of striatal DA in male mice. Consistent
of the glutamate-mediated apoptotic pathway mediated by with these findings, the GPER1 antagonist G-15 blocked
GPER1 as well as ERα as selective antagonists inhibited the effect of G-1 and partially prevented the effects of E2
this effect. Shen et al. also indicated that the ginsenoside treatment. In general, G-15–treated male mice were more
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Rg1, the primary active component of ginseng, prevents susceptible to MPTP toxicity with a greater decrease in
cognitive impairment and hippocampal neuronal apoptosis striatal DA concentration and DA transporter-specific
in a mouse model of vascular dementia, probably through binding. Furthermore, G-1 and E2 have been shown
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GPER1. In conclusion, GPER1 activation may play a key to be equally potent in promoting a shift toward an anti-
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role in the regulation of neuroinflammation by acting on inflammatory immunophenotype that reduces MPTP-
microglia, astrocytes, and cytokine release in both male induced NF-κB and iNOS activation. G-15 is also capable
and female individuals, which ultimately results in reduced of antagonizing the immunomodulatory effects of G-1,
neurodegeneration. Furthermore, it is also probably highlighting GPER1 as an immunomodulator and
beneficial for learning and memory by acting on neuronal neuroprotector in PD. Another study by Mendes-Oliveira
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development, astrocytes, and actin polymerization as well et al. demonstrated that G-1 significantly decreased the
as reducing neural apoptosis and Aβ-induced cytotoxicity phagocytic activity, expression of iNOS, and release of
(Figure 1). nitric oxide (NO) induced in N9 microglial cells after LPS
treatment. However, G-1 treatment did not decrease the
2.2. PD LPS-induced increase in the number of ionized calcium-
PD is a neurodegenerative movement disorder binding adaptor molecule 1-positive cells; it significantly
characterized by the progressive and selective loss of reduced the mRNA levels of IL-1b, cluster of differentiation
dopaminergic neurons in the substantia nigra pars 68 (CD68), and iNOS; completely inhibited DA cell
compacta. Consequently, a reduced release of striatal loss; and consequently protected the motor function
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dopamine (DA) results in the pathogenesis of PD with in male mice with PD. It was clearly demonstrated that
underlying genetic and functional causes. 88,89 It remains G-1 can modulate microglial responses and protect DA
controversial whether there exists a sex difference neurons and motor functions against lesions induced by

Volume 4 Issue 1 (2025) 5 doi: 10.36922/gpd.4632