Inhibition of Evoked Glutamate Release by Neurosteroid Allopregnanolone Via Inhibition of L-Type Calcium Channels in Rat Medial Prefrontal Cortex

Hu, Aijun; Wang, Zemin; Lan, Dan-Mei; Fu, Yingmei; Zhu, Yanhua; Dong, Yi; Zheng, Ping

doi:10.1038/sj.npp.1301261

Cited by 25 publications

(15 citation statements)

References 58 publications

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“…Notably, effects in human microglia could be blocked via L-type Ca 2+ channel inhibition (Hegg et al, 2000). AlloP may exert similar effects to regulate [Ca 2+ ] i and has been shown to dampen glutamatergic activity in mPFC via inhibition of L-type Ca 2+ channels (Hu et al, 2007). In particular, Ca v 1.2 and Ca v 1.3 L-type channels are identified as targets of AlloP inhibition (Earl & Tietz, 2011).…”

Section: Discussionmentioning

confidence: 99%

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

Paris

Zou

Hahn

et al. 2016

Brain, Behavior, and Immunity

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Human immunodeficiency virus (HIV) is associated with motor and mood disorders, likely influenced by reactive microgliosis and subsequent neural damage. We have recapitulated aspects of this pathology in mice that conditionally express the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat). Progestogens may attenuate Tat-related behavioral impairments and reduce neurotoxicity in vitro, perhaps via progesterone’s 5α-reductase-dependent metabolism to the neuroprotective steroid, allopregnanolone. To test this, ovariectomized female mice that conditionally expressed (or did not express) central HIV-1 Tat were administered vehicle or progesterone (4 mg/kg), with or without pretreatment of a 5α-reductase inhibitor (finasteride, 50 mg/kg). Tat induction significantly increased anxiety-like behavior in an open field, elevated plus maze and a marble burying task concomitant with elevated protein oxidation in striatum. Progesterone administration attenuated anxiety-like effects in the open field and elevated plus maze, but not in conjunction with finasteride pretreatment. Progesterone also attenuated Tat-promoted protein oxidation in striatum, independent of finasteride pretreatment. Concurrent experiments in vitro revealed Tat (50 nM)-mediated reductions in neuronal cell survival over 60 h, as well as increased neuronal and microglial intracellular calcium, as assessed via fura-2 AM fluorescence. Co-treatment with allopregnanolone (100 nM) attenuated neuronal death in time-lapse imaging and blocked the Tat-induced exacerbation of intracellular calcium in neurons and microglia. Lastly, neuron-glia co-cultures were labeled for Iba-1 to reveal that Tat increased microglial numbers in vitro and co-treatment with allopregnanolone attenuated this effect. Together, these data support the notion that 5α-reduced pregnane steroids exert protection over the neurotoxic effects of HIV-1 Tat.

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Section: Discussionmentioning

confidence: 99%

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

Paris

Zou

Hahn

et al. 2016

Brain, Behavior, and Immunity

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“…In the PFC, the progesterone metabolite allopregnanolone inhibits dopamine induced glutamate release ( 90 ), a mechanism that may be of special importance in relating the effects of progesterone to cognition and neuropsychiatric diseases ( 91 ). Allopregnanolone also inhibits glutamate release through an inhibition of the L-type Calcium channel ( 92 ). It has been observed that allopregnanolone, through the potentiation of GABAergic synapses, leads to a decrease in glutamate receptor efficiency ( 93 , 94 ).…”

Section: Hormone Actions In the Female Brainmentioning

confidence: 99%

Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance

Río¹,

Alliende²,

Molina³

et al. 2018

Front. Public Health

128

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Sex hormones significantly impact women's lives. Throughout the different stages of life, from menarche to menopause and all stages in between, women experience dramatic fluctuations in the levels of progesterone and estradiol, among other hormones. These fluctuations affect the body as a whole, including the central nervous system (CNS). In the CNS, sex hormones act via steroid receptors. They also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Additionally, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities. This review emphasizes the benefits a proper hormonal balance during the different stages of life has in the CNS. To achieve this goal, it is essential that hormone levels are evaluated considering a woman's age and ovulatory status, so that a correct diagnosis and treatment can be made. Knowledge of steroid hormone activity in the brain will give women and health providers an important tool for improving their health and well-being.

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“…Contrary, another Preg derivative – allopregnanolone, was reported to reduce PKA activation (a necessary upstream event) and presynaptic glutamate release in rat medial prefrontal cortex [ 110 ]. This was verified by using L-type calcium channel antagonists, verapamil and nimodipine, which blocked the effect of allopregnanolone.…”

Section: Calcium and Neurosteroidsmentioning

confidence: 99%

Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids

Rębas

Radzik

Boczek

et al. 2017

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Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.Methods: Short-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research.Results: The physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident.Conclusion: Neurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases.

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Inhibition of Evoked Glutamate Release by Neurosteroid Allopregnanolone Via Inhibition of L-Type Calcium Channels in Rat Medial Prefrontal Cortex

Cited by 25 publications

References 58 publications

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance

Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids

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