Regeneration in a Degenerating Brain: Potential of Allopregnanolone as a Neuroregenerative Agent

Abstract

Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimer’s. Among the steroids in decline, is allopregnanolone (APα), a neurosteroid metabolite of progesterone, which was found to be reduced in the serum [1,2] and plasma [3] and brain of aged vs. young subjects [4]. Further, Alzheimer disease (AD) victims showed an even further reduction in plasma and brain levels of APα relative to age-matched neurologically normal controls [1,4,5]. Our earlier work has shown that APα is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex [6]. Our ongoing research seeks to determine the neurogenic potential of APα in the triple transgenic mouse model of Alzheimer’s disease (3xTgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that neurogenic potential changes with age in nontransgenic mice and that the neurogenic profile differs between non-transgenic and 3xTgAD mice. Comparative analyses indicate that APα modifies neurogenesis in both non-transgenic and 3xTgAD mice. Preliminary data suggest that APα may modify Alzheimer’s pathology progression. Together the data indicate that APα may maintain the regenerative ability of the brain and modify progression of AD related pathology. Challenges for efficacy of regenerative agents within a degenerative milieu are discussed.

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

“…Elevation of 17βHSD/ABAD in both liver and brain would be consistent with increased metabolic conversion of APα to 5alpha-dihydrotestosterone leading to lower levels of APα in both plasma and brain. Together, these data suggest that the changes in the local biochemical milieu of neurosteroids and peptide growth factors could contribute to neurogenic deficits in early stages of AD (32,33).…”

Characterization and Expression of the Nuclear Progestin Receptor in Zebrafish Gonads and Brain1

“…The presence of Pgr proteins in the neuroendocrine regions agrees well with progestins' key functions in reproduction. However, the finding that Pgr is also present in other nonreproductive regions of the fish brain suggests that the actions of P4 extend far beyond reproduction in fish [38][39][40]. In mammals, neuronal survival, neurite outgrowth, and neurogenesis are just some of the recently identified neural functions of progestins.…”

Depression gets old fast: do stress and depression accelerate cell aging?

“…[92,94,95] Another neurosteroid, DHEA, which can have ''anticortisol'' effects (reviewed in [96] ), and which promotes psychological resilience, [51,97] has been reported to be both high and low in depression, [96] but DHEA treatment is generally reported as having significant antidepressant effects. [96] Notably, both these neurosteroids modulate HPA, [96] BDNF [96,98,99] and immune [3,[100][101][102] activity, antagonize oxidative stress [103,104] and have neuroprotective or neuroregenerative effects. [96,[98][99][100][101] Allopregnanolone also inhbits stress-induced corticotropin-releasing hormone release.…”

“…[96] Notably, both these neurosteroids modulate HPA, [96] BDNF [96,98,99] and immune [3,[100][101][102] activity, antagonize oxidative stress [103,104] and have neuroprotective or neuroregenerative effects. [96,[98][99][100][101] Allopregnanolone also inhbits stress-induced corticotropin-releasing hormone release. [99] Endogenous decreases in these neurosteroids or exogenously produced increases in their effects would be expected to have damaging or beneficial effects, respectively, in the context of depression or chronic stress.…”