Cocaine Mediated Neuroinflammation: Role of Dysregulated Autophagy in Pericytes

Susmita Sil, Fang Niu, Eric Tom, Ke Liao, Palsamy Periyasamy, Shilpa J Buch

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Cocaine, a known psychostimulant, results in oxidative stress and inflammation. Recent studies from our group have shown that cocaine induces inflammation in glial cells. Our current study was aimed at investigating whether cocaine exposure could also induce inflammation in non-glial cells such as the pericytes with a focus on the endoplasmic reticulum (ER) stress/autophagy axis. Our in vitro findings demonstrated that exposure of pericytes to cocaine resulted in upregulation of the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both the intracellular as well as extracellular compartments, thus underpinning pericytes as yet another source of neuroinflammation. Cocaine exposure of pericytes resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the autophagosome with the lysosomes. Pharmacological blocking of the sigma 1 receptor underscored its role in cocaine-mediated activation of pericytes. Furthermore, it was also demonstrated that cocaine-mediated dysregulation of autophagy involved upstream activation of the ER stress pathways, with a subsequent downstream production of pro-inflammatory cytokines in pericytes. These findings were also validated in an in vivo model wherein pericytes in the isolated brain microvessels of cocaine injected mice (7 days) exhibited increased expression of both the autophagy marker—LC3 as well as the pro-inflammatory cytokine, IL-6. This is the first report describing the role of pericytes in cocaine-mediated neuroinflammation. Interventions aimed at blocking either the sigma-1 receptor or the upstream ER stress mediators could likely be envisioned as promising therapeutic targets for abrogating cocaine-mediated inflammation in pericytes.

Original languageEnglish (US)
Pages (from-to)3576-3590
Number of pages15
JournalMolecular Neurobiology
Volume56
Issue number5
DOIs
StatePublished - May 1 2019

Keywords

  • Cocaine
  • Dysregulated autophagy
  • ER stress
  • Microvessels
  • Neuroinflammation
  • Pericytes

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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