Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease

Abstract

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

“…In animals, minocycline is lethal at very high doses (LD 50 :3600 mg/kg; Blum et al, 2004;Smith et al, 2003). In humans, long-term treatment with minocycline up to 200 mg/day is generally safe and well tolerated as In recent years, minocycline has been reported to have neuroprotective effects in various experimental neurodegenerative disease models such as cerebral ischemia (Yrjanheikki et al, 1999), traumatic brain injury (Sanchez Mejia et al, 2001), ALS (Zhu et al, 2002), PD (Wu et al, 2002), and HD (Chen et al, 2000;Wang et al, 2003). At present, a few number of studies are focused on the therapeutical potential of minocycline in AD (Hunter et al, 2004a;Seabrook et al, 2006), where it suppressed microglial production of IL-1beta, IL-6, TNF, and NGF in in vitro as well as APP transgenic mice (Seabrook et al, 2006).…”

“…In addition to its antibiotic properties, minocycline has been reported to have neuroprotective effects in various experimental models of cerebral ischemia (Yrjanheikki et al, 1999), traumatic brain injury (Sanchez Mejia et al, 2001), amyotrophic lateral sclerosis (ALS) (Zhu et al, 2002), Parkinson's diseases (PD) (Wu et al, 2002), kainic acid treatment (Heo et al, 2006), Huntington's disease (HD) (Chen et al, 2000;Wang et al, 2003), and multiple sclerosis (Popovic et al, 2002). Additionally, minocycline was reported to attenuate white matter damage in a rat model of chronic cerebral hypoperfusion .…”

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

“…Activation of microglia in turn exacerbates the neurodegenerative process. For example, mice lacking inducible nitric oxide synthase activity are resistant to MPTP-induced lesions and inhibition of microglial activation reduces MPTP neurotoxicity (Itzhak et al, 1999;Liberatore et al, 1999;Dehmer et al, 2000;Du et al, 2001;Wu et al, 2002). In the striatum and SN of 6-OHDA lesioned rat brains, prominent microglial activation was detectable weeks after the lesion (Cicchetti et al, 2002).…”

Inflammation after Intracerebral Hemorrhage

“…Evidence suggests that tetracycline derivatives provide neuroprotection against global brain ischemia (Yrjanheikki et al, 1998), amyotrophic lateral sclerosis (Van Den Bosch et al, 2002), and Parkinson disease (Wu et al, 2002a), and that this neuroprotection involves the inhibition of microglial activation. Recently, a study by Power et al (2003) demonstrated that, in a rat model of ICH, 7-day treatment with minocycline initiated 1 h after collagenase injection protected the morphology of neurons and improved functional recovery.…”