Effect of NAC treatment and physical activity on neuroinflammation in subchronic Parkinsonism; is physical activity essential?

Abstract

BackgroundNeuroprotective strategies are becoming relevant to slow down dopaminergic cell death and inflammatory processes related to the progressive neurodegeneration in Parkinson’s disease (PD). Interestingly, among others, physical activity (PA) or anti-oxidant agents (such as N-acetyl-L-cysteine, NAC) are common therapeutic strategies. Therefore, this study aims to analyze if there is a synergistic effect of physical activity along with NAC treatment on dopaminergic degeneration and neuroinflammatory response in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model after subchronic intoxication.MethodsTo ascertain this possibility, 48 8-week-old male mice (C57BL/6 strain) were used. Twenty four of them were placed individually in cages where voluntary physical activity was automatically monitored during 30 days and were divided into groups: (i) control; (ii) NAC; (iii) MPTP, and (iv) MPTP+NAC. The other 24 mice were divided into the same four groups but without physical activity.ResultsThe data collected during the treatment period showed that there was an overall increase in the total running distance in all groups under physical activity, including Parkinsonian animals. However, the monitoring data per day showed that the activity routine by MPTP and MPTP+NAC groups was disrupted by alterations in the circardian rhythm because of MPTP intoxication. Results from post-mortem studies in the substantia nigra pars compacta (SNpc) showed significant decrease in the number of TH+ cells in all MPTP groups. Moreover, TH+ expression in the striatum was significantly decreased in all MPTP groups. Thus, PA + NAC treatment do not protect dopaminergic neurons against a subchronic intoxication of MPTP. Regarding glial response, the results obtained from microglial analysis do not show significant increase in the number of Iba-1+ cell in MPTP+NAC and MPTP+PA + NAC. In the striatum, a significant decrease is observed only in the MPTP+NAC group compared with that of the MPTP group. The microglial results are reinforced by those obtained from the analysis of astroglial response, in which a decrease in the expression of GFAP+ cells are observed in MPTP+NAC and MPTP+PA + NAC compared with MPTP groups both in the SNpc and in the striatum. Finally, from the study of the astroglial response by the co-localization of GFAP/S100b, we described some expression patterns observed based on the severity of the damage produced by the MPTP intoxication in the different treated groups.ConclusionsThese results suggest that the combination of physical activity with an anti-oxidant agent does not have a synergistic neuroprotective effect in the nigrostriatal pathway. Our results show a potential positive effect, only due to NAC treatment, on the neuroinflammatory response after subchronic MPTP intoxication. Thus, physical activity is not essential, under these conditions. However, we believe that physical activity, used for therapeutic purposes, has a beneficial long-term effect. In this line, these results open the d...

Histomorphological evaluations on the frontal cortex extrapyramidal cell layer following administration of N-Acetyl cysteine in aluminum induced neurodegeneration rat model

“…Nevertheless, NAC in Group C, caused an increase in brain weight due to the glutathione synthesized by NAC activating antioxidant mechanistic mobbing off of free radicals causing the thinning of neurite thereby preventing pruning or thinning of neurites that apparently increased the density of neuron dendrites, thereby contributing to increased synaptic density and brain weight. The ameliorative effects of NAC against Aluminum induced neurodegeneration in AD model as demonstrated in this study correlates with other studies documented by (Adair et al 2001;Berk et al 2014;Giancarlo et al 2018;Gil-Martínez et al 2018). Haematoxylin and Eosin demonstration of histological layout of the extrapyramidal layer to display histological changes between AlCl 3 and neuron milieu interaction, shows marked necrosis, vacuolation in the neuropil and loss of neurite which affect synaptic plasticity in the extrapyramidal cell layer of the frontal cortex (Adair et al 2001;Berk et al 2014) as displayed in the cyto-architecture of the frontal cortex in Fig.…”

“…Sections were briefly dehydrated and cleared in xylene and air -dried. Dried sectioned were gently covered with cover slip using mounting media-DPX (Distrene Plasticizer Xylene) as described by Bancroft and Gamble (2008), Akinrinade et al 2015a, b) and Gil-Martínez et al (2018) methods.…”

“…These established NAC antioxidant defense processes (Shahripour et al 2014) have been tested in animals (Tchantchou et al 2005) and AD patients (Adair et al 2001) with evidence showing it potential to hinder oxidative tissue damage. Furthermore, Gil-Martínez et al (2018) reported NAC neuroprotective strategy associated with slowing down cell death, and neuroinflammatory response related to progression of neurodegenerative disorders such as Parkinson's disease is attributed to reduction in astroglia activity as observed in a study involving 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model. Therefore, this study was designed to demonstrate the in vivo neuroprotective effect of glutathione precursor N-acetyl cysteine (NAC) against aluminum-induced frontal cortex neurodegeneration in rat model of AD by evaluating its effects on neuro-inflamatory mechanisms involving, astrocytes (GFAP-expression), Chromaotphilic (Nissl) bodies aggregation for protein/ neurotransmitter synthesis and neuron repair following Al 3+ intoxication in rats.…”

Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

“…These effects were abolished by co-treatment with the ROS scavenger NAC, an anti-oxidant and anti-inflammatory agent [53]. It should be noted that NAC directly scavenges ROS via its sulfhydryl active group; in addition, NAC acts as a glutathione precursor which induces production of the endogenous antioxidant glutathione, thereby reducing the formation of mitochondrial reactive nitrogen species (mROS) [54]. So, NAC can ameliorate mitochondrial dysfunction and decrease oxidative stress in microglia.…”

<p>Treatment Of Magnesium-L-Threonate Elevates The Magnesium Level In The Cerebrospinal Fluid And Attenuates Motor Deficits And Dopamine Neuron Loss In A Mouse Model Of Parkinson’s disease</p>

“…It is well known that MPTP was the first agent to be distinguished for human PD. 21 By means of monoamine oxidase B in astrocytes, MPTP can be converted to MPP + after systemic administration. MPP + interferes with the flow of electrons and damages mitochondrial complex I, which cause a severe shortage in ATP formation of dopaminergic neurons transferred from the dopamine transporter.…”