Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Abstract

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

Meloxicam ameliorates motor dysfunction and dopaminergic neurodegeneration by maintaining Akt-signaling in a mouse Parkinson's disease model

“…All in all, the present results cannot exclude inhibition by COX inhibitors (including oxicams) as disease-modifying drugs for PD treatment, since both apoptotic and inflammatory pathways are involved in PD-related dopaminergic neurodegeneration [3].…”

“…In fact, acute treatment of MPTP (20 mg/kg/day x 4 days; i.p.) induces microglial activation in the mouse brain [3]. However, in a chronic MPTP-PD model using C57BL mice (30 mg/kg/day for 5 consecutive days), inflammatory responses have not been clearly observed in the substantia nigra and striatum [3].…”

“…induces microglial activation in the mouse brain [3]. However, in a chronic MPTP-PD model using C57BL mice (30 mg/kg/day for 5 consecutive days), inflammatory responses have not been clearly observed in the substantia nigra and striatum [3]. On the other hand we have recently demonstrated that oxicam NSAIDs, but not other categories of NSAIDs, elicit a neuroprotective action against MPP + -induced SH-SY5Y neuroblastoma cell death [22,23] via maintenance of phosphatidylinositol 3-kinase (PI3K)/Akt-signaling, a pathway which is independent of COX inhibition.…”

Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: Two approaches with therapeutic potential in the treatment of neurodegenerative disease

“…The principal reason is that apoptosis does not occur in the acute MPTP model (Jackson-Lewis, Jakowec, Burke, & Przedborski, 1995), whereas it does in the chronic MPTP model (Tatton & Kish, 1997). Another important difference between the two models is that a major inflammatory component occurs in the acute model, whereas it is much less in the chronic model (Furuya et al, 2004). Therefore, while it is clear that JNK plays an important role in dopamine neuron death in the presence of inflammation in the acute model, it remains to be determined if it is necessary for cell-autonomous apoptotic death within dopamine neurons.…”

Targeting of cell death and neuroinflammation with peptide-linked iron oxide nanoparticles and Gd-DTPA in a mouse model of Parkinson's disease

“…MPTP will preferentially produce an inflammatory process after an acute treatment (4 × 20 mg/kg i.p. every 2 h on one day) [19] and neuronal cell death after a chronic treatment (30 mg/kg/day during 5 consecutive days) [18,20] . The MPTP mouse model of PD and MPP + cell exposure both lead to apoptosis and TNF-α release and offer a good model for in vivo and in vitro Parkinson's studies.…”