Neurotoxicity In Mice Research Articles

Mechanistic comparison between MPTP and rotenone neurotoxicity in mice

Animal models for Parkinson’s disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. These results suggest that MPTP-induced dopaminergic neurotoxicity is more acute and specific in comparison to rotenone toxicity, and compensatory brain-derived neurotrophic factor (BDNF) induction and AMPK activation in the rotenone-treated brain might suppress the neuronal injury.

Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

Microbial treatment: the potential application for Parkinson's disease.

Alterations in the composition of the intestinal flora are associated with the pathophysiology of Parkinson's disease (PD). More importantly, the possible cause-effect links between gut flora and PD pathogenesis have been identified using PD animal models. Recent studies have found that probiotics improve the symptoms associated with constipation in PD patients. In addition, fecal microbiota transplantation (FMT) was recently shown to provide a protective effect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. Effective microbial therapy for PD includes probiotics and FMT. Therefore, microbial therapy may be a useful and novel approach for treatment of PD. In this review, I discuss the use of microbial treatment in PD.

Defining the pathogenic threat of envenoming by South African shield-nosed and coral snakes (genus Aspidelaps), and revealing the likely efficacy of available antivenom

While envenoming by the southern African shield-nosed or coral snakes (genus Aspidelaps) has caused fatalities, bites are uncommon. Consequently, this venom is not used in the mixture of snake venoms used to immunise horses for the manufacture of regional SAIMR (South African Institute for Medical Research) polyvalent antivenom. Aspidelaps species are even excluded from the manufacturer's list of venomous snakes that can be treated by this highly effective product. This leaves clinicians, albeit rarely, in a therapeutic vacuum when treating envenoming by these snakes. This is a significantly understudied small group of nocturnal snakes and little is known about their venom compositions and toxicities. Using a murine preclinical model, this study determined that the paralysing toxicity of venoms from Aspidelaps scutatus intermedius, A. lubricus cowlesi and A. l. lubricus approached that of venoms from highly neurotoxic African cobras and mambas. This finding was consistent with the cross-genus dominance of venom three-finger toxins, including numerous isoforms which showed extensive interspecific variation. Our comprehensive analysis of venom proteomes showed that the three Aspidelaps species possess highly similar venom proteomic compositions. We also revealed that the SAIMR polyvalent antivenom cross-reacted extensively in vitro with venom proteins of the three Aspidelaps. Importantly, this cross-genus venom-IgG binding translated to preclinical (in a murine model) neutralisation of A. s. intermedius venom-induced lethality by the SAIMR polyvalent antivenom, at doses comparable with those that neutralise venom from the cape cobra (Naja nivea), which the antivenom is directed against. Our results suggest a wider than anticipated clinical utility of the SAIMR polyvalent antivenom, and here we seek to inform southern African clinicians that this readily available antivenom is likely to prove effective for victims of Aspidelaps envenoming. Biological significanceCoral and shield-nosed snakes (genus Aspidelaps) comprise two species and several subspecies of potentially medically important venomous snakes distributed in Namibia, Botswana, Zimbabwe, Mozambique and South Africa. Documented human fatalities, although rare, have occurred from both A. lubricus and A. scutatus. However, their venom proteomes and the pathological effects of envenomings by this understudied group of nocturnal snakes remain uncharacterised. Furthermore, no commercial antivenom is made using venom from species of the genus Aspidelaps. To fill this gap, we have conducted a transcriptomics-guided comparative proteomics analysis of the venoms of the intermediate shield-nose snake (A. s. intermedius), southern coral snake (A. l. lubricus), and Cowle's shield snake (A. l. cowlesi); investigated the mechanism of action underpinning lethality by A. s. intermedius in the murine model; and assessed the in vitro immunoreactivity of the SAIMR polyvalent antivenom towards the venom toxins of A. l. lubricus and A. l. cowlesi, and the in vivo capability of this antivenom at neutralising the lethal effect of A. s. intermedius venom. Our data revealed a high degree of conservation of the global composition of the three Aspidelaps venom proteomes, all characterised by the overwhelming predominance of neurotoxic 3FTxs, which induced classical signs of systemic neurotoxicity in mice. The SAIMR polyvalent antivenom extensively binds to Aspidelaps venom toxins and neutralised, with a potency of 0.235 mg venom/mL antivenom, the lethal effect of A. s. intermedius venom. Our data suggest that the SAIMR antivenom could be a useful therapeutic tool for treating human envenomings by Aspidelaps species.

Signaling network between the dysregulated expression of microRNAs and mRNAs in propofol-induced developmental neurotoxicity in mice

Mounting evidence has demonstrated that general anesthetics could induce acute neuroapoptosis in developing animals followed by long-term cognitive dysfunction, with the mechanisms remaining largely unknown. The aim of this study was to investigate the effect of the intravenous anesthetic propofol on the profiles of microRNAs (miRNAs) and messenger RNAs (mRNAs), and their interactive signaling networks in the developing mouse hippocampus. Postnatal day 7 (P7) mice were exposed to propofol for 3 hours. Hippocampi were harvested from both P7 (3 hours after exposure) and P60 mice for the analysis of the expression of 726 miRNAs and 24,881 mRNAs, and apoptosis. Long-term memory ability of P60 mice was analyzed using the Morris Water Maze. Propofol induced acute apoptosis in the hippocampus, and impaired memory function of mice. There were 100 altered mRNAs and 18 dysregulated miRNAs in the propofol-treated hippocampi compared with the intralipid-treated control tissues on P7. Bioinformatics analysis of these abnormally expressed genes on P7 indicated that 34 dysregulated miRNA-mRNA target pairs were related to pathological neurological and developmental disorder processes such as cell viability, cell morphology and migration, neural stem cell proliferation and neurogenesis, oligodendrocyte myelination, reactive oxygen species, and calcium signaling. Neonatal propofol exposure also resulted in the abnormal expression of 49 mRNAs and 4 miRNAs in P60 mouse hippocampi. Specifically, bioinformatics analysis indicates that among these dysregulated mRNAs and miRNAs, there were 2 dysregulated miRNA-mRNA targets pairs (Fam46a/miR-363-3p and Rgs3/miR-363-3p) that might be related to the effect of propofol on long-term cognitive function. Collectively, our novel investigation indicates that acute and long-term dysregulated miRNA-mRNA signaling networks potentially participate in propofol-induced developmental neurotoxicity.

Effect of ceftriaxone on cognitive deficits caused by amyloid-beta neurotoxicity in mice

Effect of ceftriaxone on cognitive deficits caused by amyloid-beta neurotoxicity in mice

Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury

Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator–activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism.

Immunomodulatory effect of new quinolone derivative against cisplatin/gamma radiation-induced renal and brain toxicity in mice

Treatment of cancer often requires exposure to radiation, which has several limitations involving non-specific toxicity toward normal cells, reducing the efficacy of treatment. Recent studies synthesize new quinolone derivatives to satisfy other purposes such as treatment of inflammatory and malignant diseases. The main purpose of the present study is to evaluate the effect of a new quinolone derivative; 2-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-2-oxoacetic acid (EHQA) and its possible mechanism against gamma radiation (IRR) and cisplatin (Cis) induced nephrotoxicity and neurotoxicity in mice. The structure of the newly synthesized quinolone derivative was elucidated by microanalytical and spectral data, which were found consistent with the assigned structures. Exposure to Cis and IRR significantly induced renal damage manifested by a significant increase in levels of urea and creatinine. Moreover, the exposure to both Cis and IRR significantly decreased the levels of anti-apoptotic protein; Bcl-2 in both renal and brain tissue homogenate accompanied by activation of an inflammatory marker; IL-17. Immunophenoting results showed an activation of T- lymphocytes marker; CD3 and B-lymphocytes marker; CD19. Interperitonial administration of EHQA significantly ameliorated the above-mentioned parameters. Overall, the present results indicated that EHQA is a promising anti-inflammatory and anti-apoptotic agent. From the obtained results it can be concluded that EHQA could be a candidate as immunomodulatory agents. Further studies are required to establish its molecular mechanism.

Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-β estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABAA receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-β estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17β-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further.

Ginsenoside Re protects methamphetamine-induced dopaminergic neurotoxicity in mice via upregulation of dynorphin-mediated \u03ba-opioid receptor and downregulation of substance P-mediated neurokinin 1 receptor

BackgroundWe previously reported that ginsenoside Re (GRe) attenuated against methamphetamine (MA)-induced neurotoxicity via anti-inflammatory and antioxidant potentials. We also demonstrated that dynorphin possesses anti-inflammatory and antioxidant potentials against dopaminergic loss, and that balance between dynorphin and substance P is important for dopaminergic neuroprotection. Thus, we examined whether GRe positively affects interactive modulation between dynorphin and substance P against MA neurotoxicity in mice.MethodsWe examined changes in dynorphin peptide level, prodynorphin mRNA, and substance P mRNA, substance P-immunoreactivity, homeostasis in enzymatic antioxidant system, oxidative parameter, microglial activation, and pro-apoptotic parameter after a neurotoxic dose of MA to clarify the effects of GRe, prodynorphin knockout, pharmacological inhibition of κ-opioid receptor (i.e., nor-binaltorphimine), or neurokinin 1 (NK1) receptor (i.e., L-733,060) against MA insult in mice.ResultsGRe attenuated MA-induced decreases in dynorphin level, prodynorphin mRNA expression in the striatum of wild-type (WT) mice. Prodynorphin knockout potentiated MA-induced dopaminergic toxicity in mice. The imbalance of enzymatic antioxidant system, oxidative burdens, microgliosis, and pro-apoptotic changes led to the dopaminergic neurotoxicity. Neuroprotective effects of GRe were more pronounced in prodynorphin knockout than in WT mice. Nor-binaltorphimine, a κ-opioid receptor antagonist, counteracted against protective effects of GRe. In addition, we found that GRe significantly attenuated MA-induced increases in substance P-immunoreactivity and substance P mRNA expression in the substantia nigra. These increases were more evident in prodynorphin knockout than in WT mice. Although, we observed that substance P-immunoreactivity was co-localized in NeuN-immunreactive neurons, GFAP-immunoreactive astrocytes, and Iba-1-immunoreactive microglia. NK1 receptor antagonist L-733,060 or GRe selectively inhibited microgliosis induced by MA. Furthermore, L-733,060 did not show any additive effects against GRe-mediated protective activity (i.e., antioxidant, antimicroglial, and antiapoptotic effects), indicating that NK1 receptor is one of the molecular targets of GRe.ConclusionsOur results suggest that GRe protects MA-induced dopaminergic neurotoxicity via upregulatgion of dynorphin-mediated κ-opioid receptor and downregulation of substance P-mediated NK1 R.

Anti-hyperuricemic and neuroprotective effects of Populus nigra L. (Saliacaceae) flower buds used in Algerian folk medicine

Context: Populus nigra L., is a species of cottonwood poplar that belongs to the Salicaceae family, is cultivated in multiple areas in Algeria, with an Algerian name of Safsaf. Aims: To evaluate the Populus nigra flower buds extract for its effects on brain modifications against aluminum-induced neurotoxicity in mice. The hypouricemic action of the extract was also evaluated. Methods: To evaluate the effect of extract on AlCl3-induced neurotoxicity on mice a battery of tests was performed to assess a spectrum of learning and memory functions. The hypouricemic action of the extract was studied by the measure of uric acid levels and liver xanthine oxidoreductase activity in normal and hyperuricemic mice. Results: Co-administration of P. nigra extract (200 mg/kg) and AlCl3 (100 mg/kg/day) combined with D-galactose (200 mg/kg/day) during four weeks was found to antagonize the harmful effects of AlCl3 by restoring all the test parameters. Moreover, extract restored the pyramidal cells to near normal in cerebral cortex of mice. Extract, when administered three times orally to the normal and oxonate-induced hyperuricemic mice, was able to elicit significantly hypouricemic effect comparable to that of allopurinol. Conclusions: P. nigra flower buds extract can be considered as food enabling to antagonize AlCl3 toxicity and to control serum uric acid levels.

Preventive effect of olanzapine on trimethyltin neurotoxicity in mice: Evaluation of hippocampal neuronal loss, microglial activation, and cognitive dysfunction

Preventive effect of olanzapine on trimethyltin neurotoxicity in mice: Evaluation of hippocampal neuronal loss, microglial activation, and cognitive dysfunction

Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice

3-Fluoromethamphetamine (3-FMA) is an illegal designer drug of methamphetamine (MA) derivative. Up to date, little is known about the neurotoxic potential of 3-FMA. In the present study, we investigated the role of dopamine receptors in neurotoxicity induced by 3-FMA in comparison with MA (35 mg/kg, i.p.) as a control drug. Here we found that 3-FMA (40, 60 or 80 mg/kg, i.p.) produced mortality in a dose-dependent manner in mice. Treatment with 3-FMA (40 mg/kg, i.p.) resulted in significant hyperthermia, oxidative stress and microgliosis (microglial differentiation into M1 phenotype) followed by pro-apoptotic changes and the induction of terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL)-positive cells. Moreover, 3-FMA significantly produced dopaminergic impairments [i.e., increase in dopamine (DA) turnover rate and decreases in DA level, and in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2)] with behavioral impairments. These dopaminergic neurotoxic effects of 3-FMA were comparable to those of MA. SCH23390, a dopamine D1 receptor antagonist, but not sulpiride, a dopamine D2 receptor antagonist significantly attenuated 3-FMA-induced neurotoxicity. Although both SCH23390 and sulpiride attenuated MA-induced dopaminergic neurotoxicity, sulpiride is more effective than SCH23390 on the dopaminergic neurotoxicity. Interestingly, SCH23390 treatment positively modulated 3-FMA-induced microglial activation (i.e., SCH23390 inhibited M1 phenotype from 3-FMA insult, but activated M2 phenotype). Therefore, our results suggest that the activation of dopamine D1 receptor is critical to 3-FMA-induced neurotoxicity, while both dopamine D1 and D2 receptors (dopamine D2 receptor > dopamine D1 receptor) mediate MA-induced dopaminergic neurotoxicity.

Occurrence of cyclic imines in European commercial seafood and consumers risk assessment

Cyclic imines constitute a quite recently discovered group of marine biotoxins that act on neural receptors and that bioaccumulate in seafood. They are grouped together due to the imino group functioning as their common pharmacore, responsible for acute neurotoxicity in mice. Cyclic imines (CIs) have not been linked yet to human poisoning and are not regulated in the European Union (EU), although the European Food Safety Authority (EFSA) requires more data to perform conclusive risk assessment for consumers. Several commercial samples of bivalves including raw and processed samples from eight countries (Italy, Portugal, Slovenia, Spain, Ireland, Norway, The Netherlands and Denmark) were obtained over 2 years. Emerging cyclic imine concentrations in all the samples were analysed on a LC-3200QTRAP and LC-HRMS QExactive mass spectrometer. In shellfish, two CIs, pinnatoxin G (PnTX-G) and 13-desmethylspirolide C (SPX-1) were found at low concentrations (0.1–12µg/kg PnTX-G and 26–66µg/kg SPX-1), while gymnodimines and pteriatoxins were not detected in commercial (raw and processed) samples. In summary, SPX-1 (n: 47) and PnTX-G (n: 96) were detected in 9.4% and 4.2% of the samples, respectively, at concentrations higher than the limit of quantification (LOQ), and in 7.3% and 31.2% of the samples at concentrations lower than the LOQ (25µg/kg for SPX-1 and 3µg/kg for PnTX-G), respectively. For the detected cyclic imines, the average exposure and the 95th percentile were calculated. The results obtained indicate that it is unlikely that a potential health risk exists through the seafood diet for CIs in the EU. However, further information about CIs is necessary in order to perform a conclusive risk assessment.

17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity

Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson’s disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.

Protective effect of Zizyphus lotus jujube fruits against cypermethrin-induced oxidative stress and neurotoxicity in mice

Context: Cypermethrin (CYP) is a synthetic pyrethroid insecticide used worldwide in agriculture, home pest control. The toxicity of CYP is well studied in many organisms.Objective: The aim of present study was to investigate the protective effect of Zizyphus lotus (Zizyp) fruit against neurotoxicity and oxidative stress induced by CYP in mice.Materials and methods: Mice were divided into four groups of six each: groups I and II were used as control and CYP control (20 mg/kg body weight). While, groups III was orally treated with Zizyphus lotus fruit (5 g/kg body weight) plus CYP (20 mg/kg body weight) for 18 days. Furthermore, HPLC–ESI–MS–MS (Q-Tof) and GC–MS were used to identify the compounds fraction.Results: Antioxidant enzyme catalase (CAT), neurotoxicity enzyme acetylcholinesterase (AChE) activities and hydrogen peroxide (H2O2), malondialdehyde (MDA) levels were determined in the liver, kidney and heart. CYP caused decreased CAT activity, inhibition of AChE activity and increased the levels of H2O2 and MDA in heart, liver and kidney.Conclusion: Our results indicate that Zizyp fruit is markedly effective in protecting mice against CYP-induced biochemical changes. This protection may be due to its antioxidant property and scavenging ability against active free radicals.

In situ different antioxidative systems contribute to the site-specific methylmercury neurotoxicity in mice

Methylmercury (MeHg), an environmental toxicant, induces site-specific neurotoxicity in adult human and animal models. In this study, we demonstrated that MeHg-induced neuropathological changes of the brain in mice were remarkable in the cerebrocortical neurons of deeper layers (dl-CCNs), but not in the CCNs of shallow layers (sl-CCNs) and the hippocampal neurons of cornu ammonis 1 (CA1-HNs). Total mercury concentration was not corresponded to the pathological changes. Here, we investigated the cause of such site-specific MeHg neurotoxicity with a focus on in situ antioxidative systems due to its critical role in MeHg intoxication. We performed in situ analyses of antioxidative enzymes expression using RT-qPCR analyses from laser microdissected sl-CCNs, dl-CCNs, and CA1-HNs samples, and immunohistochemistry. The results of antioxidative enzymes expression analyses demonstrated the lowest basal expression levels of mRNA and proteins, especially manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase 1 (GPx1) in dl-CCNs. In addition, the Mn-SOD expression showed a lowest response to MeHg in dl-CCNs. We also performed enzymatic activity analyses for antioxidative enzymes using separated cerebral cortex and hippocampus. The results of enzymatic activity analyses indicate that the expression levels of antioxidative enzymes reflect their enzymatic activities. Immunostaining of thymidine glycerol, a sensitive oxidative stress marker, showed selectively increased expression in dl-CCNs after the exposure to MeHg but not in sl-CCNs and CA1-HNs, suggesting the occurrence of MeHg-induced oxidative stress in dl-CCNs. The differences in MeHg-induced occurrence of oxidative stress and pathological changes in sl-CCNs, dl-CCNs, and CA1-HNs corresponded to the basal level of Mn-SOD and GPx1 expression and the different protective response of Mn-SOD expression to MeHg. These findings suggest that the in situ different antioxidative systems play a role in the site-specific neurotoxicity of MeHg.

Separating the agony from ecstasy: R(–)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

S,R(+/–)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.

Compound X alleviates the neuronal loss induced by A-SYN aggregates

Background: Parkinson’s disease (PD) is the second-most common neurodegenerative disease. Accumulation of misfolded alpha-synuclein (a-syn), called Lewy body, is a histological hallmark of PD. It is widely believed that aggregated a-syn plays a central role for disease onset and progression. Medications such as L-Dopa and dopamine agonists are effective for motor symptoms, but there is still no disease modifying drug for PD. Compound X was first identified as a novel substance which promotes proliferation of neural stem cells. So far, we have found that Compound X alleviates MPTP-induced neurotoxicity in mice.

ANTIOXIDANT PROPERTIES OF DICHROCEPHALA INTEGRIFOLIA (ASTERACEAE) IN A MOUSE MODEL OF MONOSODIUM GLUTAMATE-INDUCED NEUROTOXICITY

Background: In Africa, neurodegenerative diseases in the elderly have become a major health concern due to the increase
 in live expectancy. Glutamate mediated neurotoxicity is involved in neurodegenerative diseases such as Ischemia, Epilepsy,
 Alzheimer’s and Parkinson diseases. Plants with antioxidant properties are reported to protect vital organs against
 glutamate toxicity. This study aims to assess the effect of Dichrocephala integrifolia against monosodium glutamatemediated
 neurotoxicity and oxidative stress.
 Methodology: The decoction prepared from the leaves of Dichrocephala integrifolia was evaluated against monosodium
 glutamate-induced neurotoxicity in mice. The animals were grouped in seven groups of 6 animals each. The animals
 received daily; distilled water (p.o) for the distilled water and the negative control groups, one of the four doses of the
 decoction of the plant (35, 87.5, 175 or 350 mg/kg p.o) for the tests groups and memantine (20 mg/kg p.o) for the positive
 control group. Monosodium glutamate (2.5 g/kg ip) was injected daily to animals except those of the normal control group
 all the seven days of the experimentation. Animals were observed for aggressiveness, locomotor and forepaws muscle grip
 activities 30 min after monosodium injections. Brain reduced glutathione and malondialdehyde levels were also assessed
 following the behavioral tests on day 8.
 Results: The decoction of Dichrocephala integrifolia at the doses of 87.5 and 175 mg/kg significantly (p