Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system

Abstract

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferatoractivated receptor gamma (PPAR-c) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-c agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

“…6A, B, E and F). Because inflammation induces mitochondrial dysfunction in vitro and in vivo (Hunter et al, 2007) and « is an important index of mitochondrial function, the effects of U0126 and rapamycin on the LL-37-mediated protection of « in LPS-induced inflammatory response were examined. Rapamycin and LL-37 siRNA but not the ERK inhibitor U0126 neutralized the protective effects of LL-37 and produced a low « (Fig.…”

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

“…Chronic inflammation plays a role in the pathogenesis of Parkinson's disease (PD) [25], and several lipopolysaccharide (LPS)-induced PD models [3,19,22,30] have focused on inflammation's role in PD-related neurodegeneration. In these models, LPS activates microglia, increases oxidative stress, impairs mitochondrial function, and induces what appears to be specific dopaminergic neurodegeneration [19,22].…”

“…In these models, LPS activates microglia, increases oxidative stress, impairs mitochondrial function, and induces what appears to be specific dopaminergic neurodegeneration [19,22]. Pioglitazone, an agonist of peroxisome proliferator activated receptor-γ (PPAR-γ), can prevent LPS-induced dopaminergic neurodegeneration [22], and may be useful as a PD treatment [21].…”

“…In these models, LPS activates microglia, increases oxidative stress, impairs mitochondrial function, and induces what appears to be specific dopaminergic neurodegeneration [19,22]. Pioglitazone, an agonist of peroxisome proliferator activated receptor-γ (PPAR-γ), can prevent LPS-induced dopaminergic neurodegeneration [22], and may be useful as a PD treatment [21]. However, little is known about the mechanistic effects of pioglitazone, which in addition to its anti-inflammatory properties may also affect mitochondrial uncoupling proteins [23] and bioenergetics [12,22].…”

Protection Against Parkinson’s Disease Progression: Clinical Experience

“…For example, the oncological drug taxol, 113 anti-inflammatory medications, 114,115 and a drug for multiple sclerosis, glatimer, 116 have each shown therapeutic promise in animal models of parkinsonism. Istradefylline (KW-6002), a xanthine-based antagonist of the adenosine A 2A receptor (and which has symptomatic effects on PD for parkinsonism), has also been effective for improving recovery in a neurotoxin-induced animal model of parkinsonism.…”