Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide

A massive degeneration of dopamine-containing neurons in the substantia nig ra (SN) in the midbrain is characteristic of Parkinson's disease. Inflammat ion in the brain has long been speculated to play a role in the pathogenesi s of this neurological disorder. Recently, we reported that treatment of pr imary rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS) led to the activation of microglia, resident immune cells of the brai n, and subsequent death of dopaminergic neurons. The LPS-induced degenerati on of dopaminergic neurons was significantly attenuated by the opiate recep tor antagonist (-)-naloxone and its inactive isomer (+)- naloxone, with equ al potency, through an inhibition of microglial activation and their produc tion of neurotoxic factors. In this study, injection of LPS into the rat SN led to the activation of microglia and degeneration of dopaminergic neuron s: microglial activation was observed as early as 6 h and loss of dopaminer gic neurons was detected 3 days after the LPS injection. Furthermore, the L PS-induced loss of dopaminergic neurons in the SN was time- and LPS concent ration-dependent. Systemic infusion of either (-)-naloxone or (+)-naloxone inhibited the LPS-induced activation of microglia and significantly reduced the LPS-induced loss of dopaminergic neurons in the SN. These in vivo resu lts combined with our cell culture observations confirmed that naloxone pro tects dopaminergic neurons against inflammation-mediated degeneration throu gh inhibition of microglial activation and suggest that naloxone would have therapeutic efficacy in the treatment of inflammation-related neurological disorders. In addition, the inflammation-mediated degeneration of dopamine rgic neurons in the rat SN resulting from the targeted injection of LPS may serve as a useful model to gain further insights into the pathogenesis of Parkinson's disease.