Abstract
Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke.
Highlights
Steroid hormones are synthesized by adrenal glands, gonads, and placenta and influence the function of many target tissues including the nervous system
In addition to the novo synthesis of neurosteroids from cholesterol, some steroids can be locally converted in the nervous system to neuroactive metabolites, as in the case of progesterone which is metabolized into 3α,5α-tetrahydroprogesterone (3α,5α-THPROG; allopregnanolone)
This review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain
Summary
Steroid hormones are synthesized by adrenal glands, gonads, and placenta and influence the function of many target tissues including the nervous system. Some steroids are synthesized de novo by neurons and glial cells and are called “neurosteroids” to refer to their site of synthesis: the nervous system [1]. In addition to the novo synthesis of neurosteroids from cholesterol, some steroids can be locally converted in the nervous system to neuroactive metabolites, as in the case of progesterone which is metabolized into 3α,5α-tetrahydroprogesterone (3α,5α-THPROG; allopregnanolone). Progesterone and its metabolite 3α,5α-THPROG have been extensively studied in brain, spinal cord, and sciatic nerve, and have been shown to regulate several functions including myelination, neuroprotection, and neuropathic pain [8,9,10,11,12,13]. This review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain
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