No abstract

Global cerebral ischemia can elicit rapid innate neuroprotective mechanisms that protect against delayed neuronal death. Brain-derived 17β-estradiol (BDE2), an endogenous neuroprotectant, is synthesized from testosterone by the enzyme aromatase (Aro) and is upregulated by brain ischemia and inflammation. Our recent study revealed that G1, a specific G-protein-coupled estrogen receptor 1 (GPER) agonist, exerts anti-inflammatory and anti-apoptotic roles after global cerebral ischemia (GCI). Herein, we aimed to elucidate whether G1 modulates the early inflammatory process and the potential underlying mechanisms in the ovariectomized rat hippocampal CA1 region. G1 was found to markedly reduce pro-inflammatory (iNOS, MHCII, and CD68) and to enhance anti-inflammatory (CD206, Arginase 1, IL1RA, PPARγ, and BDNF) markers after 1 and 3 days of reperfusion after GCI. Intriguingly, the neuroprotection of G1 was blocked by the Aro inhibitor, letrozole. Conversely, the GPER antagonist, G36, inhibited Aro-BDE2 signaling and exacerbated neuronal damage. As a whole, this work demonstrates a novel anti-inflammatory role of GPER, involving a synergistic mediation with BDE2 during the early stage of GCI.

Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age.

Despite extensive astrocyte activation in patients suffering from HIV-associated neurocognitive disorders (HAND), little is known about the contribution of astrocytes to HAND neuropathology. Here, we report that the robust activation of neurotoxic astrocytes (A1 astrocytes) in the CNS promotes neuron damage and cognitive deficits in HIV-1 gp120 transgenic mice. Notably, knockout of α7 nicotinic acetylcholine receptors (α7nAChR) blunts A1 astrocyte responses, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. Furthermore, we provide evidence that Kynurenic acid (KYNA), a tryptophan metabolite with α7nAChR inhibitory property, attenuates gp120-induced A1 astrocyte formation through blockade of α7nAChR/JAK2/STAT3 signaling activation. Meanwhile, compared with gp120tg mice, mice fed with tryptophan showed dramatic improvement in cognitive performance, which was related to the inhibition of A1 astrocyte responses. These initial and determinant findings mark a turning point in our understanding of the role of α7nAChR in gp120-mediated A1 astrocyte activation, which opens new opportunities to control neurotoxic astrocyte generation through KYNA and tryptophan administration.