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Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide.
J Pharmacol Exp Ther. 2000 Oct; 295(1):125-32.JP

Abstract

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.

Authors+Show Affiliations

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. liu3@niehs.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10991969

Citation

Liu, B, et al. "Systemic Infusion of Naloxone Reduces Degeneration of Rat Substantia Nigral Dopaminergic Neurons Induced By Intranigral Injection of Lipopolysaccharide." The Journal of Pharmacology and Experimental Therapeutics, vol. 295, no. 1, 2000, pp. 125-32.
Liu B, Jiang JW, Wilson BC, et al. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther. 2000;295(1):125-32.
Liu, B., Jiang, J. W., Wilson, B. C., Du, L., Yang, S. N., Wang, J. Y., Wu, G. C., Cao, X. D., & Hong, J. S. (2000). Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. The Journal of Pharmacology and Experimental Therapeutics, 295(1), 125-32.
Liu B, et al. Systemic Infusion of Naloxone Reduces Degeneration of Rat Substantia Nigral Dopaminergic Neurons Induced By Intranigral Injection of Lipopolysaccharide. J Pharmacol Exp Ther. 2000;295(1):125-32. PubMed PMID: 10991969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. AU - Liu,B, AU - Jiang,J W, AU - Wilson,B C, AU - Du,L, AU - Yang,S N, AU - Wang,J Y, AU - Wu,G C, AU - Cao,X D, AU - Hong,J S, PY - 2000/9/19/pubmed PY - 2001/2/28/medline PY - 2000/9/19/entrez SP - 125 EP - 32 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 295 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10991969/Systemic_infusion_of_naloxone_reduces_degeneration_of_rat_substantia_nigral_dopaminergic_neurons_induced_by_intranigral_injection_of_lipopolysaccharide_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10991969 DB - PRIME DP - Unbound Medicine ER -