Neurotoxicity In Mouse Model Research Articles

Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus.

It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and verification. The aims of this study were to clarify the molecular mechanism underlying PTX-induced neurotoxicity by combining in vivo and in vitro metabolomics studies and provide new targets for the prevention and treatment of PTX-induced neurotoxicity. In the in vivo study, a PTX-induced neurotoxicity mouse model was established by intraperitoneal injection of PTX (6 mg/kg every three days) for two consecutive weeks. After verification by water maze tests and HE staining of pathological sections, hippocampal metabolites were measured and the differential metabolites and related metabolic pathways were identified by multivariate statistical analysis. In the in vitro study, we investigated the effects of PTX on mouse hippocampal neuron cells, assessing the concentration and time of administration by MTT assays. After modeling, the relevant metabolites in the TCA cycle were quantified by targeted metabolomics using stable isotope labeling. Finally, the key enzymes of the TCA cycle in tissues and cells were verified by RT-PCR. Administration of PTX to model mice resulted in neurological damage, shown by both water-maze tests and hippocampal tissue sections. Twenty-four metabolites and five associated metabolic pathways were found to differ significantly between the hippocampal tissues of the model and control groups. These included metabolites and pathways related to the TCA cycle and pyruvate metabolism. Metabolomics analysis using stable isotope labeling showed significant changes in metabolites associated with the TCA cycle compared with the control group (P < 0.05). Finally, RT-PCR verified that the expression of key enzymes in the TCA cycle was changed to different degrees in both hippocampal tissues and cells. Our results showed that PTX neurotoxicity in hippocampal tissue and neuron cells was associated with inhibition of the TCA cycle. This inhibition leads to brain insufficiency and impaired metabolism, resulting in various neurotoxic symptoms.

Protective effects of chrysin against the neurotoxicity induced by aluminium: In vitro and in vivo studies

Chronic exposure to aluminium (Al) can contribute to the progression of several neurological and neurodegenerative diseases. Al is a metal that promotes oxidative damage leading to neuronal death in different brain regions with behavior, cognition, and memory deficits. Chrysin is a flavonoid found mainly in honey, passion fruit, and propolis with antioxidant, anti-inflammatory, and cytoprotective properties. In this study, we used an integrated approach of in vitro and in vivo studies to evaluate the antioxidant and neuroprotective effects of chrysin against the neurotoxicity elicited by aluminium chloride (AlCl3). In in vitro studies, chrysin (5 μM) showed the ability to counteract the early oxidative stress elicited by tert-butyl hydroperoxide, an oxidant that mimics the lipid peroxidation and Fenton reaction in presence of AlCl3 as well as the late necrotic death triggered by AlCl3 in neuronal SH-SY5Y cells. In vivo studies in a mouse model of neurotoxicity induced by chronic exposure to AlCl3 (100 mg/kg/day) for ninety days then corroborated the antioxidant and neuroprotective effect of chrysin (10, 30, and 100 mg/kg/day) using the oral route. In particular, chrysin reduced the cognitive impairment induced by AlCl3 as well as normalized the acetylcholinesterase and butyrylcholinesterase activities in the hippocampus. In parallel, chrysin counteracted the oxidative damage, in terms of lipid peroxidation, protein carbonylation, catalase, and superoxide dismutase impairment, in the brain cortex and hippocampus. Lastly, necrotic cells frequency in the same brain regions was also decreased by chrysin. These results highlight the ability of chrysin to prevent the neurotoxic effects associated with chronic exposure to Al and suggest its potential use as a food supplement for brain health.

Mnemonic and neuroprotective properties of Sclerocarya birrea root bark decoction on mouse model of monosodium glutamate-induced neurotoxicity involve by its antioxidant activities

Ethnopharmacological relevance: Sclerocarya birrea (A. Rich.) Hochst. (Anacardiaceae) is a medicinal plant known for the treatment of several diseases such as epilepsy, hypertension, inflammation and memory disorders in Cameroonian folk medicine. Aim of the study: The aim of this work is to evaluate the memory improvement and neuroprotective effects of Sclerocarya birrea aqueous root bark extracts and investigate it antioxidant properties. Materials and methods: T-maze and the object recognition test in an open field were used for behavioral testing to detect its neuroprotective and memory improvement properties. The DPPH test was used to predict antioxidant activities in vitro. The in vivo antioxidant activities of the aqueous extracts were investigated using the Monosodium glutamate induced oxidative stress and neurotoxicity mouse model. After the behavioral testing, animals were decapitated and the brains were removed for oxidative stress biomarkers determination. Results: Sclerocarya birrea decreased the preferred arm choice latency and the time spent in the discriminated, in the T-maze. It increased exploration time and recognition index, and decreased the latency to explore the new object B. In addition, Sclerocarya birrea increased the superoxide dismutase and catalase activities, and reduced glutathione level. Conclusion: These results suggest that Sclerocarya birrea possess neuroprotective and mnemonic activities in mice that might involve by its free radicals scavenging properties

Expression of DnMTs and MBDs in AlCl3-Induced Neurotoxicity Mouse Model.

Alteration in DNA methylation after aluminum exposure has been shown to contribute in pathogenesis of Alzheimer's disease (AD). This study is aimed to determine the effect of Al exposure (42 and 60days) on learning and memory and the expression of proteins involved in DNA methylation (MBD1, MBD2, MBD3, MeCP2 (methyl CpG binding protein 2), DnMT1 and DnMT3a). Male BALB/c mice were treated with AlCl3 for either 42days or 60days. After treatment completion, learning and memory were compared to the control group using novel object recognition test, elevated plus maze test, open field test, and Morris water maze test. The treated animals and their respective controls were sacrificed after cognitive testing and samples from their whole cortex and hippocampus were harvested for gene expression analysis. Mice treated with AlCl3 showed significant cognitive deficit with impaired short-term memory, elevated anxiety, and deterioration in spatial and reference memory. The AlCl3 treatment showed significant reduction in the expression of MBDs in the whole cortex at 60days of treatment as compared to control. AlCl3-treated animals showed decreased expression of MBDs and DnMT3a in the hippocampus for longer treated animals but strikingly, MBD2 showed significantly increased expression in AlCl3-treated animals at 60days p ≤ 0.001. In conclusion, this study showed that AlCl3-treated animals showed significant memory and cognitive deficits and it is associated with significant changes in the expression of proteins involved in DNA methylation mechanism. Moreover, different Al exposure duration had slightly different effects.

Methylphenidate and Rosmarinus officinalis improves cognition and regulates inflammation and synaptic gene expression in AlCl3-induced neurotoxicity mouse model.

Methylphenidate (MPH), a psychotropic medication is commonly used for children with attention deficit hyperactivity disorder (ADHD). In this study we elucidated the neuroprotective and anti-inflammatory effects of MPH and Rosmarinus officinalis (rosemary) extract, an ancient aromatic herb with several applications in traditional medicine. Briefly, six groups of mice (n = 8 each group), were specified for the study and behavioral analysis was performed to analyze spatial memory followed by histological assessment and gene expression analysis of synaptic (Syn I, II and III) and inflammatory markers (IL-6, TNFα and GFAP) via qRT-PCR, in an AlCl3-induced mouse model for neurotoxicity. The behavioral analysis demonstrated significant cognitive decline, memory defects and altered gene expression in AlCl3-treated group. Rosemary extract significantly decreased the expression of inflammatory and synaptic markers to the similar levels as that of MPH. The present findings suggested the neuroprotective potential of Rosmarinus officinalis extract. However, further characterization of its anti-inflammatory and neuroprotective properties and MPH is required to strategize future treatments for several neurological and neurodegenerative disorders, including Alzheimer's disease.

Styphnolobium japonicum (L.) Schott Fruits Increase Stress Resistance and Exert Antioxidant Properties in Caenorhabditis elegans and Mouse Models.

Styphnolobium japonicum (L.) Schott is a popular Asian tree widely used in traditional medicine. The current study explored the potential stress resistance and antioxidant activities of its fruits. Phytochemical profiling of the hydroalcoholic fruit extract was done via high performance liquid chromatography-photodiode array-electrospray ionization-mass/mass (HPLC-PDA-ESI-MS/MS). Twenty four phenolic constituents were tentatively identified in the extract. The Caenorhabditis elegans (C. elegans) nematode model in addition to trimethyltin (TMT)-induced neurotoxicity mouse model were used for in vivo evaluation of its antioxidant properties. The ability of the extract to enhance stress resistance was manifested through increasing survival rate by 44.7% and decreasing basal reactive oxygen species (ROS) levels by 72.3% in C. elegans. In addition, the extract increased the levels of the stress response enzyme superoxide dismutase-3 (Sod-3) by 55.5% and decreased the expression of heat shock protein-16.2 (Hsp-16.2) in nematodes, which had been challenged by juglone, by 21%. Using a mouse model, the extract significantly decreased the expression of the oxidative stress marker malondialdehyde (MDA). Furthermore, an elevation in the levels of the antioxidant marker glutathione (GSH), SOD and heme oxygenase-1 (HO-1) enzymes were observed. Our findings imply that Styphnolobium japonicum has the potential to be used in future studies focusing on diseases associated with oxidative stress.

HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity.

Parkinson's disease is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra and iron accumulation in the substantia nigra. The driver underlying iron accumulation remains unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for Parkinson's disease. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants.

HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity

Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss and iron accumulation in the substantia nigra (SN). The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild‐type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R2 relaxation rate within the substantia nigra of the paraquat‐treated mice compared to their saline‐treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in L‐ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants.Support or Funding InformationThe work is supported in part by the Pennsylvania Department of Health Tobacco CURE Funds and the Penn State Neuroscience Institute.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.

Memory Enhancing Effect of Black Pepper in the AlCl3 Induced Neurotoxicity Mouse Model is Mediated Through Its Active Component Chavicine.

Black pepper (Piper nigrum Linn.) has vital pharmacological properties with profound effects on central nervous system. Neurotoxic agents like Aluminum Chloride (AlCl3) cause the oxidative stress and result in improper processing of amyloid proteins leading to accumulation of amyloid β plaques. The study aimed to explore the neuroprotective potential of black pepper (BP) extract (12.5mg/kg/day) on memory enhancement and its effect on expression of amyloid precursor protein (APP) isoforms (APP770 and APP695) in AlCl3 induced neurotoxicity (250mg/kg) mouse model. The study included the isolation and identification of pure compound from BP (chavicine) which was found pharmacologically active. Morris water maze test, elevated plus maze, fear conditioning, context and cue dependent test and social preference tests were performed to investigate the learning and memory. Gene expression (APP isoforms) and in-vitro and ex-vivo DPPH free radical scavenging activity were performed to evaluate the role of BP. BP significantly improved memory in AlCl3 induced neurotoxicity mouse model along with effectively decreasing the expression of APP770 (amyloidogenic) isoform and improved level of APP695 (non-amyloidogenic) in hippocampus, amygdala and cortex. Fear extinction learning was considerably improved in BP treated group (7.83±2.03) than AlCl3 induced neurotoxicity group (39.75±4.25). In the hippocampus, BP significantly reduced the expression of APP770 (0.37±0.05) as compared to AlCl3 induced neurotoxicity group (0.72±0.06), and effectively increased (34.80±1.39) the percentage inhibition of DPPH free radicals as compared to AlCl3 induced neurotoxicity group (14±2.68). The study revealed that BP improves memory and chavicine is a lead compound producing pharmacological effects of BP.

Memory-enhancing effect of aspirin is mediated through opioid system modulation in an AlCl3-induced neurotoxicity mouse model.

Neurodegenerative disorders such as Alzheimers disease (AD) are multifaceted and there are currently a limited number of therapeutic strategies available to treat them. Aspirin is known to act on multiple therapeutic targets and is a successful anti-inflammatory agent in various tissues. The present study aimed to ascertain the performance of aspirin when employed as a therapeutic agent to treat neurodegeneration on novel targets, including opioid system genes, in an AlCl3-induced neurotoxicity mouse model. The effects of two doses of aspirin (5 and 20 mg/kg aspirin for 12 days) were investigated in an AlCl3-induced neurotoxicity mouse model (150 mg/kg AlCl3 for 12 days). Neurological improvements were assessed through different behavioral tests and the effects of aspirin on opioid system gene expression levels were assessed by reverse transcription-polymerase chain reaction. Both doses resulted in improvements in cognitive behavior. A 5 mg/kg dose of aspirin was revealed to be effective for spatial memory improvement (7.14±0.84 sec), whilst a 20 mg/kg dose was superior for improving extinction learning (7.63±4.04%). Aspirin (5 mg/kg) also significantly improved contextual memory (48.05±10.6%) when compared with the AlCl3-treated group (1.49±0.62%; P<0.001). Aspirin was also observed to significantly decrease δ-opioid receptor expression in the cortex (1.09±0.08 and 1.27±0.08, respectively) at both doses (5 and 20 mg/kg) when compared with the AlCl3-treated group (3.69±1.43; P<0.05). Furthermore, aspirin at 5 mg/kg significantly reduced expression of prodynorphin in the cortex (0.57±0.20) when compared with the AlCl3-treated group (1.95±0.84; P<0.05). Notably, the effect of aspirin was significant in the cortex but not in the hippocampus. In summary, aspirin was effective in ameliorating the AD-like symptoms via the modulation of opioid systems. However, additional studies are required to determine the long term effects of aspirin on such conditions.

Alpha-lipoic acid-mediated activation of muscarinic receptors improves hippocampus- and amygdala-dependent memory

Aluminum (Al) is a neurotoxic agent which readily crosses the blood-brain-barrier (BBB) and accumulates in the brain leading to neurodegenerative disorders, characterised by cognitive impairment. Alpha-lipoic acid (ALA) is an antioxidant and has a potential to improve cognitive functions. This study aimed to evaluate the neuroprotective effect of ALA in AlCl3-induced neurotoxicity mouse model. Effect of ALA (25mg/kg/day) was evaluated in the AlCl3-induced neurotoxicity (AlCl3 150 mg/kg/day) mouse model on learning and memory using behaviour tests and on the expression of muscarinic receptor genes (using RT-PCR), in hippocampus and amygdala. Following ALA treatment, the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase (ChaT) were significantly improved (p<0.05) relative to AlCl3-treated group. ALA enhanced fear memory (p<0.01) and social novelty preference (p<0.001) comparative to the AlCl3-treated group. Fear extinction memory was remarkably restored (p<0.001) in ALA-treated group demonstrated by reduced freezing response as compared to the AlCl3-treated group which showed higher freezing. In-silico analysis showed that racemic mixture of ALA has higher binding affinity for M1 and M2 compared to acetylcholine. These novel findings highlight the potential role of ALA in cognitive functions and cholinergic system enhancement thus presenting it an enviable therapeutic candidate for the treatment of neurodegenerative disorders.

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity.

Aluminum is known to exert neurotoxic effects associated with various neurodegenerative disorders, including Alzheimer's disease (AD). Ibuprofen is a well-known non-steroidal anti-inflammatory drug, which has demonstrated potential efficacy in the treatment of numerous inflammatory and neurodegenerative disorders, including AD. The present study aimed to investigate the protective effects of ibuprofen on cognitive function, and the expression levels of neuronal pentraxins (NPs) and interleukin (IL)-1β in an aluminum chloride (AlCl3)-induced mouse model of neurotoxicity. The effects of ibuprofen (100 mg/kg/day for 12 days) on learning and memory were evaluated in the AlCl3-induced neurotoxic mice using a Morris water maze and open field tests. In addition, ibuprofen was assessed for its effects on the expression levels of NPs and IL-1β in the hippocampus, cortex and amygdala of the brain. Treatment of the AlCl3-treated mice with ibuprofen decreased anxiety levels (6.90±0.34 min) compared with the AlCl3-treated group (1.80±0.29 min), as indicated by the time spent in the central area in an open field test. Furthermore, the expression levels of NP1 (1.32±0.47) and IL-1β (0.99±0.21) were significantly decreased in the hippocampus of mice following ibuprofen treatment, as compared with the AlCl3-treated mice (8.62±1.54 and 7.47±0.53, respectively). In the present study, ibuprofen was able to target novel structures in order to attenuate the inflammation associated with an AlCl3-induced mouse model of neurotoxicity; thus suggesting that ibuprofen may be considered a potential therapeutic option for the treatment of neurodegenerative diseases, including AD.

Cyclooxygenase I and II inhibitors distinctly enhance hippocampal- and cortex-dependent cognitive functions in mice.

Cyclooxygenase (COX) enzymes are expressed in the brain; however, their role in hippocampus-dependent and cortex-dependent cognitive functions remains to be fully elucidated. The aim of the present study was to comparatively investigate the effects of piroxicam, a selective COX-I inhibitor, and celecoxib, a selective COX‑II inhibitor, on cognitive functions in an AlCl3‑induced neurotoxicity mouse model to understand the specific role of each COX enzyme in the hippocampus and cortex. The AlCl3 (250 mg/kg) was administered to the mice in drinking water and the drugs were administered in feed for 30 days. Assessments of memory, including a Morris water maze, social behavior and nesting behavior were performed in control and treated mice. The RNA expression of the COX enzymes were analyzed using reverse transcription‑quantitative polymerase chain reaction analysis. An ex‑vivo 2,2‑Diphenyl‑1‑picrylhydrazyl assay was performed in the hippocampus and cortex. Following 30 days of treatment with thedrugs, the mice in the celecoxib‑ and piroxicam‑treated groups exhibited enhanced learning (6.84 ± 0.76 and 9.20 ± 1.08, respectively), compared with the AlCl3‑induced neurotoxicity group (21.14 ± 0.76) on the fifth day of the Morris water maze test. Celecoxib treatment improved social affiliation in the AlCl3‑induced neurotoxicity group, the results of which were superior to piroxicam. Piroxicam led to better improvement in nesting score in the AlCl3‑induced neurotoxicity group. Both drugs decreased the expression levels of COX‑I and COX‑II in the hippocampus and cortex, and rescued oxidative stress levels. These findings suggested that each drug distinctly affected cognitive functions, highlighting the distinctive roles of COX-I and COX-II in learning and memory.

Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke

Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30mg/kgbwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse.

Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity.

Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into “reactive” phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both signal through STAT3 but appear to do so through different modules, perhaps localized to different cell types.

Diphenyl diselenide administration enhances cortical mitochondrial number and activity by increasing hemeoxygenase type 1 content in a methylmercury-induced neurotoxicity mouse model

Interest in biochemistry of organoselenium compound has increased in the last decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of diphenyl diselenide (PhSe)2 (5 μmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Swiss male mice were divided into four experimental groups: control, (PhSe)2 (5 μmol/kg, subcutaneous administration), MeHg (40 mg/L, in tap water), and MeHg + (PhSe)2. After the treatment (21 days), the animals were killed and the cerebral cortex was analyzed. Electron microscopy indicated an enlarged and fused mitochondria leading to a reduced number of organelles, in the MeHg-exposed mice. Furthermore, cortical creatine kinase activity, a sensitive mitochondrial oxidative stress sensor, was almost abolished by MeHg. Subcutaneous (PhSe)2 co-treatment rescued from MeHg-induced mitochondrial alterations. (PhSe)2 also behaved as an enhancer of mitochondrial biogenesis, by increasing cortical mitochondria content in mouse-receiving (PhSe)2 alone. Mechanistically, (PhSe)2 (1 μM; 24 h) would trigger the cytoprotective Nrf-2 pathway for activating target genes, since astroglial cells exposed to the chalcogen showed increased content of hemeoxygenase type 1, a sensitive marker of the activation of this via. Thus, it is proposed that the (PhSe)2-neuroprotective effect might be linked to its mitoprotective activity.

Protective Effect of Arctigenin against MPP+ and MPTP-induced Neurotoxicity

The potential protective effects of arctigenin on 1-methyl-4-phenylpyridinium ion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity were examined, and the results indicated that arctigenin could improve the movement behaviors and upregulate dopamine and γ-aminobutyric acid levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity mouse model. A further in vitro experiment showed that the pretreatment with arctigenin on cultured human neuroblastoma SH-SY5Y cells could obviously attenuate the decrease of cell survival rates caused by treatment with 1-methyl-4-phenylpyridinium ion by way of acting against cell apoptosis through the decrease of Bax/Bcl-2 and caspase-3, and by antioxidative action through reduction of the surplus reactive oxygen species production and downregulation of mitochondrial membrane potential. It is for the first time that a neuroprotective activity of arctigenin in both in vitro and in vivo experiments was reported, enlightening that arctigenin could be useful as a potential therapeutic agent for Parkinson's disease.

Mildronate improves cognition and reduces amyloid‐β pathology in transgenic Alzheimer's disease mice

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-β deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-β pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients.

Mildronate enhances learning/memory and changes hippocampal protein expression in trained rats

Previously we demonstrated that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a representative of the aza-butyrobetaine class of compounds, protects mitochondrial metabolism under conditions such as ischemia. Mildronate also acted as a neuroprotective agent in an azidothymidine-induced mouse model of neurotoxicity, as well as in a rat model of Parkinson's disease. These observations suggest that mildronate may stimulate processes involved in cell survival and change expression of proteins involved in neurogenic processes. The present study investigated the influence of mildronate on learning and memory in the passive avoidance response (PAR) test and the active conditioned avoidance response (CAR) test in rats. The CAR test employed also bromodeoxyuridine (BrdU)-treated animals. Hippocampal cell BrdU incorporation was then immunohistochemically assessed in BrdU-treated, CAR-trained rats to identify proliferating cells. In addition, the expression of hippocampal proteins which could serve as memory enhancement biomarkers was evaluated and compared to non-trained animals' data. These biomarkers included glutamic acid decarboxylase 65/67 (GAD65/67), acetylcholine esterase (AChE), growth-associated protein-43 (GAP-43) and the transcription factor c-jun/activator protein-1 (AP-1). The results showed that mildronate enhanced learning/memory formation that coincided with the proliferation of neural progenitor cells, changing/regulating of the expression of biomarker proteins which are involved in the activation of glutamatergic and cholinergic pathways, transcription factors and adhesion molecule.The data from our study suggest that mildronate may be useful as a possible cognitive enhancer for the treatment of patients with neurodegenerative diseases with dementia.