Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta

Abstract

Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP(+) levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP.

The Effect of Docosahexaenoic Acid on Visual Evoked Potentials in a Mouse Model of Parkinson’s Disease: The Role of Cyclooxygenase-2 and Nuclear Factor Kappa-B

“…In this study, MPTP administration lead to an increase of in COX -2 activity which strongly suggests that it plays a detrimental role in neurodegeneration and stimulation of an inflammatory process following neuronal death (Przybylkowski et al 2004;Boyd et al 2007). Cyclooxygenase-2 may aggravate the degeneration process (Hoang et al 2009) which also plays an important role in MPTP toxicity.…”

“…DHA groups received four intraperitoneal injections (20 9 4 mg/kg) of freshly prepared MPTP-HCl (M-0896, Sigma-Aldrich, St. Louis, Mo, USA) in saline at 2-h intervals for MPTP intoxication (Hunot et al 2004;Boyd et al 2007). Control and DHA groups received equivalent volume injections of saline.…”

Genetic correlational analysis reveals no association between MPP+ and the severity of striatal dopaminergic damage following MPTP treatment in BXD mouse strains

“…Our observation that the association between MPP + production and a reduction in measures of striatal DA terminal integrity was weak or nonexistent was unexpected. But it should be noted that others also have reported strain differences in MPTP neurotoxicity that were not related to MPP + levels (Boyd et al, 2007 ). We also found little to no association between MPP + levels and the GFAP response to striatal dopaminergic terminal damage in the BXD strains, i.e., the strains with the most damage did not have the highest levels of MPP + .…”

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

“…Furthermore, other factors which must be considered are the strain and sex of animals utilized for the studies. Selective sensitivity to the neurotoxin has been demonstrated in distinct background strains of mice, a phenomenon due, at least in part, to differences in activation of subcellular pathways that mediate degeneration, including JNK and cJun [36][37][38][39] . Sex-dependent differences in MPTP toxicity have also been reported 40,41 , and may contribute to variability in studies using transgenic mice in which both sexes are used for poor-breeding lines.…”

“…Typically, higher doses of the toxicant are used to produce robust nigral dopaminergic cell loss and striatal dopamine depletion 23,24,32,[36][37][38]39 . It is important to note that toxicity of MPTP can vary between vendors and lots; consequently doses may need to be adjusted to produce the desired lesion.…”