Golexanolone affords sustained improvement of Parkinson's symptoms in rats by reducing microglia activation that restores the glutamate-GABA-dopamine pathway

Golexanolone improves motor and non-motor symptoms in the 6-OHDA rat model of Parkinson’s disease (PD) and reduces neuroinflammation in the striatum, without inducing dyskinesias. To understand the underlying mechanisms, we hypothesized that activated microglia in substantia nigra (SN) have increased glutaminase and glutamate production; glutamate uptake by astrocytes induces GABA release and enhanced GABA A receptors activation contributes to loss of tyrosine hydroxylase (TH) and dopamine. The study aims were to assess if: 1) the mechanisms proposed occur and are reversed by golexanolone; 2) improvement by golexanolone is maintained with pathological progression; 3) an earlier treatment start provides more beneficial effects. Daily golexanolone treatment from one week after model induction by unilateral injection of 6-OHDA in male rats was performed. Motor function, fatigue and short-term memory were assessed after four and eight weeks. At three and nine weeks, TH, glutamate and dopamine, as well as glutaminase in microglia and GABA in astrocytes were analysed. 6-OHDA rats show microglia activation in SN, with increased glutaminase and glutamate. Increased glutamate is associated with reduced GABA into astrocytes and increased extracellular GABA, which enhances GABA A receptors activation in neurons, contributing to loss of TH and dopamine, and altering TrkB signaling. Golexanolone reduces activation of microglia at early and long time after 6-OHDA injection, reduces activation of the glutaminase-glutamate-GABA-TH-dopamine pathway at three weeks after surgery and preserves TrkB membrane expression associated with dopamine receptors, despite the loss of dopamine, at a longer time. Both mechanisms contribute to sustained improvement of fatigue and motor and cognitive functions. Early treatment affords more beneficial effects than late treatment on PD symptoms. Golexanolone affords sustained improvement of PD symptoms in the rat model by reducing neuroinflammation, increasing dopaminergic signalling and therefore could be considered for clinical evaluation in patients with PD.