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Vol. 295, Issue 1, 125-132, October 2000
Neuropharmacology Section, Laboratory of Pharmacology and
Chemistry, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina (B.L., B.C.W., J.-S.H.); State
Key Laboratory of Medical Neurobiology, Shanghai Medical University,
Shanghai, China (J.-W.J., L.D., G.-C.W., X.-D.C.); and National Defense
Medical Center, Taipei, Taiwan (S.-N.Y., J.-Y.W.)
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.
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