Regeneration in a degenerating brain: Potential of allopregnanolone as a neuroregenerative agent

Ming Wang Jun, Ronald W. Irwin, Lifei Liu, Shuhua Chen, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 nontransgenic 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.

Original languageEnglish (US)
Pages (from-to)510-517
Number of pages8
JournalCurrent Alzheimer Research
Volume4
Issue number5
DOIs
StatePublished - Dec 2007
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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