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Neuroprotection of α-synuclein under acute and chronic rotenone and maneb treatment is abolished by its familial Parkinson's disease mutations A30P, A53T and E46K

Choong CJ, Say YH

Neurotoxicology, 2011 Dec;32(6):857-63.
PMID: 21658409 DOI: 10.1016/j.neuro.2011.05.012

α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). α-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of α-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial α-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type α-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant α-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type α-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type α-Syn may be protective, and such property may be lost by its familial PD mutations.
Distribution of PON1 polymorphisms PON1Q192R and PON1L55M among Chinese, Malay and Indian males in Singapore and possible susceptibility to organophosphate exposure

Chia SE, Mohamed Ali S, Yap PH, Gan L, Ong YB, Chia KS

Neurotoxicology, 2009 Mar;30(2):214-9.
PMID: 19135476 DOI: 10.1016/j.neuro.2008.12.004

Organophosphate (OP)-containing pesticides are widely used worldwide for domestic and industrial purposes. Studies on acute and chronic exposure to OPs have revealed numerous health effects attributed mainly to acetylcholinesterase (AChE) inhibition. The enzyme human serum paraoxonase (PON1) is involved in the detoxification of OP compounds. PON1 polymorphisms have been shown to affect susceptibility to OP exposure. We studied the effect of OP exposure on pest control workers and assessed the distribution of two common PON1 polymorphisms in our local population. The exposed group consisted of 103 workers from various pest control companies under the Singapore Pest Management Association while the 91 unexposed workers were from a lead stabilizer factory. For all workers, the mean age was 36.9 (20-70) years and the ethnic distribution was 38.1% Chinese, 44.3% Malay and 17.5% Indian. The mean+/-S.D. exposure duration among the pesticide workers was 10.4+/-8.4 years. The mean+/-S.D. RBC cholinesterase level was 18436.2+/-2078U/L and 18079.6+/-1576U/L for the exposed and unexposed groups, respectively (p=0.216). The mean+/-S.D. serum pseudocholinesterase was 11028.4+/-2867.4U/L and 9433.6+/-2022.6U/L in the exposed and unexposed groups, respectively (p<0.0001). Mean paraoxonase activity was similar among Chinese and Malays (266.5 and 266.3U/L, respectively) whereas that of the Indians was significantly lower (165.6U/L). Our study showed that cholinesterase levels among the exposed were not lower than those in the unexposed group. PON1 polymorphisms differed among ethnic groups, implying that ethnicity could be an important surrogate for identifying susceptible groups in case of OP exposure. Although OP poisoning is rare among occupationally exposed workers in Singapore, this information is useful for other developing countries that have large populations of Chinese, Malays and Indians where OP exposure could be very high especially in agricultural settings.
Our recent experiences with sarin poisoning cases in Japan and pesticide users with references to some selected chemicals

Yokoyama K

Neurotoxicology, 2007 Mar;28(2):364-73.
PMID: 16730798

Attention has been paid to neurobehavioral effects of occupational and environmental exposures to chemicals such as pesticides, heavy metals and organic solvents. The area of research that includes neurobehavioral methods and effects in occupational and environmental health has been called "Occupational and Environmental Neurology and Behavioral Medicine." The methods, by which early changes in neurological, cognitive and behavioral function can be assessed, include neurobehavioral test battery, neurophysiological methods, questionnaires and structured interview, biochemical markers and imaging techniques. The author presents his observations of neurobehavioral and neurophysiological effects in Tokyo subway sarin poisoning cases as well as in pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness (GTS). In sarin cases, a variety effects were observed 6-8 months after exposure, suggesting delayed neurological effects. Studies on pesticide users revealed that organophosphorus and dithiocarbamate affected peripheral nerve conduction and postural balance; subjective symptoms related to GTS were also observed, indicating the effects of nicotine absorbed from wet tobacco leaves. In addition, non-neurological effects of pesticides and other chemicals are presented, in relation to genetic polymorphism and oxidative stress.
Neuroprotective effects of glucomoringin-isothiocyanate against H2O2-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells

Jaafaru MS, Nordin N, Rosli R, Shaari K, Bako HY, Saad N, et al.

Neurotoxicology, 2019 12;75:89-104.
PMID: 31521693 DOI: 10.1016/j.neuro.2019.09.008

Neurodegenerative diseases (NDDs) are pathological conditions characterised by progressive damage of neuronal cells leading to eventual loss of structure and function of the cells. Due to implication of multi-systemic complexities of signalling pathways in NDDs, the causes and preventive mechanisms are not clearly delineated. The study was designed to investigate the potential signalling pathways involved in neuroprotective activities of purely isolated glucomoringin isothiocyanate (GMG-ITC) against H2O2-induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. GMG-ITC was isolated from Moringa oleifera seeds, and confirmed with NMR and LC-MS based methods. Gene expression analysis of phase II detoxifying markers revealed significant increase in the expression of all the genes involved, due to GMG-ITC pre-treatment. GMG-ITC also caused significant decreased in the expression of NF-kB, BACE1, APP and increased the expressions of IkB and MAPT tau genes in the differentiated cells as confirmed by multiplex genetic system analysis. The effect was reflected on the expressed proteins in the differentiated cells, where GMG-ITC caused increased in expression level of Nrf2, SOD-1, NQO1, p52 and c-Rel of nuclear factor erythroid factor 2 (Nrf2) and nuclear factor kappa-B (NF-kB) pathways respectively. The findings revealed the potential of GMG-ITC to abrogate oxidative stress-induced neurodegeneration through Nrf2 and NF-kB signalling pathways.
Antiapoptotic effect of taurine against NMDA-induced retinal excitotoxicity in rats

Lambuk L, Iezhitsa I, Agarwal R, Bakar NS, Agarwal P, Ismail NM

Neurotoxicology, 2019 01;70:62-71.
PMID: 30385388 DOI: 10.1016/j.neuro.2018.10.009

OBJECTIVE: N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure.
METHODOLOGY: Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with PBS and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure respectively. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique.
RESULTS: Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 μm length (by 1.5-fold, p
The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis

Chan EWL, Krishnansamy S, Wong C, Gan SY

Neurotoxicology, 2019 01;70:91-98.
PMID: 30408495 DOI: 10.1016/j.neuro.2018.11.001

The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Aβ) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1β, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38α MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3β and p38α MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1β secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.
Remarkable migration propensity of dental pulp stem cells towards neurodegenerative milieu: An in vitro analysis

Senthilkumar S, Venugopal C, Parveen S, K S, Rai KS, Kutty BM, et al.

Neurotoxicology, 2020 12;81:89-100.
PMID: 32905802 DOI: 10.1016/j.neuro.2020.08.006

Stem cell therapy provides a ray of hope for treating neurodegenerative diseases (ND). Bone marrow mesenchymal stem cells (BM-MSC) were extensively investigated for their role in neuroregeneration. However, drawbacks like painful bone marrow extraction, less proliferation and poor CNS engraftment following systemic injections of BM-MSC prompt us to search for alternate/appropriate source of MSC for treating ND. In this context, dental pulp stem cells (DPSC) could be an alternative to BM-MSC as it possess both mesenchymal and neural characteristic features due to its origin from ectoderm, ease of isolation, higher proliferation index and better neuroprotection. A study on the migration potential of DPSC compared to BM-MSC in a neurodegenerative condition is warranted. Given the neural crest origin, we hypothesize that DPSC possess better migration towards neurodegenerative milieu as compared to BM-MSC. In this prospect, we investigated the migration potential of DPSC in an in vitro neurodegenerative condition. Towards this, transwell, Matrigel and chorioallantoic membrane (CAM) migration assays were carried-out by seeding hippocampal neurons in the lower chamber and treated with 300 μM kainic acid (KA) for 6 h to induce neurodegeneration. Subsequently, the upper chamber of transwell was loaded with DPSC/BM-MSC and their migration potential was assessed following 24 h of incubation. Our results revealed that the migration potential of DPSC/BM-MSC was comparable in non-degenerative condition. However, following injury the migration potential of DPSC towards the degenerating site was significantly higher as compared to BM-MSC. Furthermore, upon exposure of naïve DPSC/BM-MSCs to culture medium derived from neurodegenerative milieu resulted in significant upregulation of homing factors like SDF-1alpha, CXCR-4, VCAM-1, VLA-4, CD44, MMP-2 suggesting that the superior migration potential of DPSC might be due to prompt expression of homing factors in DPSC compared to BM-MSCs.
In vitro cytotoxicity assessment of ruxolitinib on oligodendrocyte precursor cell and neural stem/progenitor cell populations

Lim CW, Hamanaka G, Liang AC, Chan SJ, Ling KH, Lo EH, et al.

Neurotoxicology, 2024 Aug 28;105:10-20.
PMID: 39209271 DOI: 10.1016/j.neuro.2024.08.004

JAK-STAT signaling cascade has emerged as an ideal target for the treatment of myeloproliferative diseases, autoimmune diseases, and neurological disorders. Ruxolitinib (Rux), is an orally bioavailable, potent and selective Janus-associated kinase (JAK) inhibitor, proven to be effective to target activated JAK-STAT pathway in the diseases previously described. Unfortunately, limited studies have investigated the potential cytotoxic profile of Rux on other cell populations within the heterogenous CNS microenvironment. Two stem and progenitor cell populations, namely the oligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NSPCs), are important for long-term maintenance and post-injury recovery response of the CNS. In light of the limited evidence, this study sought to investigate further the effect of Rux on proliferating and differentiating OPCs and NSPCs populations. In the present study, cultured rat OPCs and NSPCs were treated with various concentrations of Rux, ranging from 2 μM to 20 μM. The effect of Rux on proliferating OPCs (PDGF-R-α+) and proliferating NSPCs (nestin+) was assessed via a 3-day Rux treatment, whereas its effect on differentiating OPCs (MBP+/PDGF-R-α+) and differentiating NSPCs (neurofilament+) was assessed after a 7-day treatment. Cytotoxicity of Rux was also assessed on OPC populations by examining its influence on cell death and DNA synthesis via YO-PRO-1/PI dual-staining and BrdU assay, respectively. The results suggest that Rux at a dosage above 10 μM reduces the number proliferating OPCs, likely via the induction of apoptosis. On the other hand, Rux treatment from 2.5 μM to 20 μM significantly reduces the number of differentiating OPCs by inducing necrosis. Meanwhile, Rux treatment has no observable untoward impact on NSPC cultures within the dosage range tested. Taken together, OPCs appears to be more vulnerable to the dosage effect of Rux, whereas NSPCs are not significantly impacted by Rux, suggesting a differential mechanism of actions of Rux on the cell types.