Unexpected Exacerbation of Neuroinflammatory Response After a Combined Therapy in Old Parkinsonian Mice

Abstract

The design of therapeutic strategies that focus on the repositioning of anti-inflammatory and antioxidant drugs are a great bet to slow down the progression of neurodegenerative disorders. Despite the fact that Parkinson’s disease (PD) is an age-related pathology, almost all experimental studies are carried out in young animals. Here, we evaluated the possible neuroprotective effect of the combination of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory HA-1077 in aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (C57BL/6 mice, 20 months old), whose individual treatment has been shown to have neuroprotective effects in this Parkinsonism model. Interestingly, NAC+HA-1077-based treatment produced a significant increase in dopaminergic neuronal death accompanied by an increase in microglial and astroglial activation in the Substantia Nigra pars compacta (SNpc) and striatum of old-Parkinsonian mice compared to their control group. The astroglial response was also explored by co-immunostaining for GFAP and S100b together with p-JNK and it was found to be particularly exacerbated in the MPTP+NAC+HA-1077 group. The unexpected toxic effects found in the combined use of NAC and HA-1077 in old-Parkinsonian mice highlight the importance of taking into account that in elderly Parkinsonian patients the combination of some drugs (most of them used for other different age-related alterations) can have side effects that may result in the exacerbation of the neurodegenerative process.

A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity

“…In each slice, four images per hemisphere and striatal area were taken at 20× magnification. Quantification of the TH immunoreactivity in striatal fibers was assessed by optical density using Fiji software, applying a plug-in for color deconvolution for DAB stainings [ 9 , 67 ].…”

“…Once inside the cell, MPP+ induces the disruption of the mitochondrial electron chain, which triggers oxidative stress and neurotoxic effects, with neuronal death as a result [ 8 ]. Additionally, several studies have shown that MPTP also induces an exacerbated inflammatory response, which has been shown to be a key element in neurodegeneration [ 9 , 10 , 11 ].…”

Withania somnifera influences MDMA-induced hyperthermic, cognitive, neurotoxic and neuroinflammatory effects in mice

“…Collectively, the results obtained here in glial cells substantiate the hypothesis first suggested by Thomas and colleagues [55] on a role for microglial and astroglial activation in the neurotoxicity mediated by amphetamine-related drugs. Thus, several studies have demonstrated that astroglial and microglial activation may sustain neurodegeneration in the dopaminergic nigrostriatal system [56], and this mechanism has also been proposed to participate in the neurotoxic dopaminergic damage induced by MDMA [30].…”

Emerging role of S100B protein implication in Parkinson’s disease pathogenesis

“…However, intraperitoneal treatment for 14 days with zonisamide, an antiepileptic agent that was shown to improve PD symptoms in clinical trials [80], has been demonstrated to be accompanied by increased astrocytic S100B levels in the basal ganglia of 6-OHDAtreated mice [81]. The combined treatment of the antioxidant N-acetylcysteine and the anti-inflammatory agent HA-1077 has been associated with enhanced dopaminergic death and astrocytic activation accompanied by elevated S100B expression in MPTP-treated mice [82]. Therefore, treatment approaches against PD may diversely affect S100B levels, probably depending on the specific molecular processes underlying each therapeutic strategy.…”