RT Journal Article
SR Electronic
T1 Systemic Infusion of Naloxone Reduces Degeneration of Rat Substantia Nigral Dopaminergic Neurons Induced by Intranigral Injection of Lipopolysaccharide
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 125
OP 132
VO 295
IS 1
A1 Bin Liu
A1 Jian-Wei Jiang
A1 Belinda C. Wilson
A1 Lina Du
A1 San-Nan Yang
A1 Jiz-Yuh Wang
A1 Gen-Cheng Wu
A1 Xiao-Ding Cao
A1 Jau-Shyong Hong
YR 2000
UL http://jpet.aspetjournals.org/content/295/1/125.abstract
AB A massive degeneration of dopamine-containing neurons in the substantia nigra (SN) in the midbrain is characteristic of Parkinson's disease. Inflammation in the brain has long been speculated to play a role in the pathogenesis of this neurological disorder. Recently, we reported that treatment of primary rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS) led to the activation of microglia, resident immune cells of the brain, and subsequent death of dopaminergic neurons. The LPS-induced degeneration of dopaminergic neurons was significantly attenuated by the opiate receptor antagonist (−)-naloxone and its inactive isomer (+)-naloxone, with equal potency, through an inhibition of microglial activation and their production of neurotoxic factors. In this study, injection of LPS into the rat SN led to the activation of microglia and degeneration of dopaminergic neurons: microglial activation was observed as early as 6 h and loss of dopaminergic neurons was detected 3 days after the LPS injection. Furthermore, the LPS-induced loss of dopaminergic neurons in the SN was time- and LPS concentration-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 results combined with our cell culture observations confirmed that naloxone protects dopaminergic neurons against inflammation-mediated degeneration through 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 dopaminergic 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. U.S. Government