Micrandilactone C, a Nortriterpenoid Isolated from Roots of Schisandra chinensis, Ameliorates Huntington’s Disease by Inhibiting Microglial STAT3 Pathways

Abstract

Huntington’s disease (HD) is a neurodegenerative disease that affects the motor control system of the brain. Its pathological mechanism and therapeutic strategies have not been fully elucidated yet. The neuroprotective value of micrandilactone C (MC), a new schiartane nortriterpenoid isolated from the roots of Schisandra chinensis, is not well-known either. Here, the neuroprotective effects of MC were demonstrated in 3-nitropropionic acid (3-NPA)-treated animal and cell culture models of HD. MC mitigated neurological scores and lethality following 3-NPA treatment, which is associated with decreases in the formation of a lesion area, neuronal death/apoptosis, microglial migration/activation, and mRNA or protein expression of inflammatory mediators in the striatum. MC also inhibited the activation of the signal transducer and activator of transcription 3 (STAT3) in the striatum and microglia after 3-NPA treatment. As expected, decreases in inflammation and STAT3-activation were reproduced in a conditioned medium of lipopolysaccharide-stimulated BV2 cells pretreated with MC. The conditioned medium blocked the reduction in NeuN expression and the enhancement of mutant huntingtin expression in STHdhQ111/Q111 cells. Taken together, MC might alleviate behavioral dysfunction, striatal degeneration, and immune response by inhibiting microglial STAT3 signaling in animal and cell culture models for HD. Thus, MC may be a potential therapeutic strategy for HD.