Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1‐dependent mitochondrial fission

Abstract

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and βIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.