Impact of microglial depletion through colony-stimulating factor 1 receptor inhibition on demyelination and neurodegeneration in a chronic cuprizone-induced demyelination model

VICTORIA S.B. WIES MANCINI, ANABELLA A. DI PIETRO, SOLEDAD DE OLMOS, JUANA M. PASQUINI, JORGE D. CORREALE, LAURA A. PASQUINI

Cordoba

Congreso; XXXIV Annual Meeting of the Argentine Society for Research in Neuroscience (SAN); 2019

SAN

Cuprizone (CPZ)-induced demyelination is widely used as a multiple sclerosis (MS) model to study de/remyelination processes. Microglia (MG) participates in demyelination and neurodegeneration processes, and is physiologically dependent on colony-stimulating factor 1 receptor (CSF-1R) signaling. Aim: to evaluate the effects of brain-penetrant CSF-1R inhibitor, BLZ945, on remyelination and neuroregeneration in mice submitted to chronic CPZ demyelination. Mice were fed either control or CPZ (0.2% w/w) chow for twelve weeks, and orally gavaged vehicle or BLZ945 (200 mg/kg/day) from the second week of CPZ treatment (C, BLZ945, CPZ and CPZ+BLZ945). Results showed that BLZ945 induces a significant reduction in the number of microglia in all structures evaluated. BLZ945 treatment attenuates demyelination in corpus callosum (CC), Striatum (ST), Fimbria (F), Splenium CC External (SCCE) and Cerebellum (CE). A significant positive amimo-cupric-silver (ACS) staining was particularly prominent in axons traversing the ST and in fibers throughout the CC, ECC, F and CE in both CPZ and CPZ+BLZ945 mice, which is still larger in ST and CC in CPZ+BLZ945 mice. Strikingly, this axonal degeneration was accompanied of terminal axonal ovoids characteristic of inflammatory demyelination. In contrast ACS staining was hardly ever observed in axonal terminal puncta at synaptic sites and individual stained neuron cell bodies. Taking together, these results indicate: 1) neurodegeneration is not exclusively consequence of demyelination, and 2) though microglial depletion could prevent demyelination, it could exacerbate axonal degeneration. These results could be transferred to the treatment of progressive forms of MS.