Neurosteroid and neurotransmitter alterations in Parkinson's disease

Parkinson's disease (PD) is associated with a massive loss of dopaminergic cells in the substantia nigra leading to dopamine hypofunction and alteration of the basal ganglia circuitry. These neurons, are under the control, among others, of the excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. An imbalance between these systems may contribute to excitotoxicity and dopaminergic cell death. Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of several neurotransmitter systems. The substantia nigra of the human brain expresses high concentrations of allopregnanolone (3α, 5αtetrahydroprogesterone), a neurosteroid that positively modulates the action of GABA at GABA_A receptors and of 5α-dihydroprogesterone, a neurosteroid acting at the genomic level. This article reviews the roles of NS acting as neuroprotectants and as GABA_A receptor agonists in the physiology and pathophysiology of the basal ganglia, their impact on dopaminergic cell activity and survival, and potential therapeutic application in PD.