Modulation of peroxisome proliferator‐activated receptor‐α activity by N‐acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures

Abstract

Glial cells secrete proinflammatory mediators in the brain in response to exogenous stimuli such as infection and injury. Previously, we documented that systemic maternal lipopolysaccharide (LPS)-exposure at embryonic gestation day 18 causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by N-acetyl cysteine (NAC; precursor of glutathione). The present study delineates the underlying mechanism of NAC-mediated attenuation of inhibition of OL development in LPS-stimulated mixed glial ) of OL-progenitors. Correspondingly, an impairment of peroxisomal proliferation was shown by a decrease in the level of peroxisomal proteins in the developing OLs following exposure to LPS-conditioned media (LCM). Both NAC and WY14643, a peroxisome proliferatoractivated receptor (PPAR)-a agonist attenuated these LCMinduced effects in OL-progenitors. Similar to WY14643, NAC attenuated LCM-induced inhibition of PPAR-a activity in developing OLs. Studies conducted with cytokines and diamide (a thiol-depleting agent) confirmed that cytokines are active agents in LCM which may be responsible for inhibition of OL development via peroxisomal dysfunction and induction of oxidative stress. These findings were further corroborated by similar treatment of developing OLs generated from PPAR-a ()/)) and wild-type mice or B12 oligodendroglial cells co-transfected with PPAR-a small interfering RNAs/ pTK-PPREx3-Luc plasmids. Collectively, these data provide evidence that the modulation of PPAR-a activity, thus peroxisomal function by NAC attenuates LPS-induced glial factorsmediated inhibition of OL development suggesting new therapeutic interventions to prevent the devastating effects of maternal infections. Keywords: cerebral white matter injury, lipopolysaccharide, oligodendrocyte, peroxisome proliferator-activated receptor-a and N-acetyl cysteine, reactive oxygen species.

Olig1 is expressed in human oligodendrocytes during maturation and regeneration

“…Although PPARa is expressed in oligodendrocytes (Kainu et al, 1994), the PPARa null mutant appears normal (Lee et al, 1995), and a PPARa agonist has no obvious effects on oligodendrocyte maturation (Paintlia et al, 2008). It was beyond the scope of this study to detect PPARa expression.…”

N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action

“…21 Furthermore, lipopolysaccharide treatment results in inhibited oligodendroglial cell development and myelination that is attenuated by NAC administration in rat mixed glial cultures. 22 The reductions in inflammatory cytokines by NAC treatment may be a potential mechanism by which NAC modulates the symptoms of psychiatric disorders. This may be directly associated with the inflammatory pathway, or working through oxidative processes associated with inflammation.…”

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

“…NAC pretreatment prevents loss of long-term potentiation and oxidative stress after exposure to prenatal inflammation (Lante et al 2008). Lipopolysaccharide treatment inhibits oligodendroglial cell myelination and development which is attenuated by administration of NAC (Paintlia et al 2008). In the light of the literature previously highlighted on the nexus between inflammation and the genesis of depression, the effects of NAC on inflammatory cytokines may be a potential mechanism whereby NAC may impact depression.…”