Abstract
Microglial activation is implicated in the pathogenesis of Parkinson’s disease (PD). Although the etiology of PD remains unclear, age and male gender are known PD risk factors. By comparing microglia and dopaminergic (DA) neurons in the substantia nigra (SN) of male and female mice of different ages, we found that the degrees of microglial activation and DA neuron loss increased with age in both genders, but were more pronounced in males, as were peripheral lipopolysaccharide (LPS)-induced microglial activation and DA neuron loss. A bilateral ovariectomy (OVX) eliminated the female-associated protection against age- and LPS-induced microglial activation, which suggests that ovary hormones are involved in gender-specific responses. Treating female mice with 17β-estradiol supplements reduced the age-associated microglial activation in OVX mice. Moreover, pretreating mouse BV2 microglial cells with 17β-estradiol inhibited LPS-induced elevation of Toll-like receptor 4, phosphorylated p38, and TNF-α levels. We then examined the effect of 17β-estradiol on inward-rectifier K+ channel Kir2.1, a known regulator of microglial activation. We found that 17β-estradiol inhibited the Kir2.1 activity of BV2 cells by reducing the probability that the channel would be open. We conclude that age- and inflammation-associated microglial activation is attenuated by ovarian estrogen, because it inhibits Kir2.1.
Highlights
Information of estrogen-induced neuronal responses, the physiological function of estrogen in other brain cells, such as microglia, is less clear
After examining the effects of gender on age- and inflammation-induced microglial activation and DA neuron loss in the substantia nigra (SN) of mice, we found that they were higher with age in both genders and more pronounced in males, as were peripheral LPS-induced microglial activation and subsequent DA neuron loss
The female-related protections against age- and LPS-associated injuries were eliminated by an OVX, and E2 supplements reversed OVX-induced microglial activation and DA neuron loss in female mice
Summary
Information of estrogen-induced neuronal responses, the physiological function of estrogen in other brain cells, such as microglia, is less clear. The term “resting microglia” is misleading because resting microglia are always dynamic[19,20,21] After they have been exposed to certain stimulatory signals, microglia activate in order to execute innate immune functions[20,21,22]. This includes changes in morphology, gene expression, and functional behavior[21,22]. Kir2.1, which is constitutively expressed in microglia and macrophages, helps to maintain a negative membrane potential, which regulates the influx of Ca2+ and subsequent signaling pathways associated with microglial activation[24,30]. The role of Kir2.1 in the estrogen-induced regulation of microglia was examined. The effect of E2 on microglial activation was investigated in a BV2 mouse microglial cell line
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