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.