Neurosteroids as regenerative agents in the brain: therapeutic implications.

TitleNeurosteroids as regenerative agents in the brain: therapeutic implications.
Publication TypeJournal Article
Year of Publication2013
AuthorsBrinton RD
JournalNat Rev Endocrinol
Date Published2013 Apr
KeywordsAlzheimer Disease, Animals, Brain, Humans, Neurotransmitter Agents, Pregnanolone

Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. The challenge faced by researchers developing molecular therapeutics to promote self-renewal in the nervous system is to activate regenerative and repair pathways often in the context of progressive degeneration. Neurosteroids regulate both regeneration and repair systems in the brain, and among this class of molecules, allopregnanolone has been broadly investigated for its role to promote regeneration in both the central and peripheral nervous systems. In the brain, allopregnanolone induced generation and survival of new neurons in the hippocampus of both aged mice and mice with Alzheimer disease, accompanied by restoration of associative learning and memory function. In the brain of mice with Alzheimer disease, allopregnanolone increased liver X receptor and pregnane X receptor expression, reduced amyloid-β and microglial activation, and increased markers of myelin and white matter generation. Therapeutic windows for efficacy of allopregnanolone were evident in the brains of mice with both normal ageing and Alzheimer disease. Allopregnanolone dose and a regenerative treatment regimen of intermittent allopregnanolone exposure were determining factors regulating therapeutic efficacy. Allopregnanolone serves as proof of concept for therapeutics that target endogenous regeneration, windows of therapeutic opportunity for regeneration, and critical system biology factors that will determine the efficacy of regeneration.

Alternate JournalNat Rev Endocrinol
PubMed ID23438839
Grant ListU01 AG031115 / AG / NIA NIH HHS / United States
UL1 RR031986 / RR / NCRR NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D