Dopaminergic neurons and microglia shift in mice induced- by CCl4

Abstract

There is growing evidence showing that chronic liver diseases, often accompanied by liver inflammation and fibrosis, are not limited to the liver, but comprise several organs, especially the brain. Moreover, recent epidemiological studies revealed a strong relationship between Parkinsonism and several liver diseases. In the present work, we used a liver inflammation model, induced by carbon tetrachloride (CCl4). CCl4 is metabolized by the hepatocytes to form the toxic trichloromethyl radical (CCl•3), which disrupts the lipid metabolism in the liver. In this hepatic inflammation model, we analyzed the pathological changes in midbrain neurons and microglia using immunohistochemistry and 2-photon microscopy. CCl4 was given over three different periods (36 hours, 4, and 9 weeks) to mimic both the acute and the chronic phases of inflammation. The data revealed surprisingly early (36 hours after the first CCl4 injection) signs of microglial activation in both SNr and SNc but not in the VTA and moderate but significant and selective loss of dopaminergic neurons in the SNc after both 4- and 9-week-long CCl4 treatments. The latter, however, was not accompanied by abnormalities in motor behaviour. Together, these findings suggest that microglia, activated right at the beginning of liver-mediated inflammation, might trigger/cause the loss of dopaminergic neurons in SNc. The parkinsonian symptoms might be the consequence.