Neurochemistry International

BackgroundEpidemiologic study suggests nicotine reduces risk of PD, could be potential treatment for Parkinsons disease. ObjectiveTo study the effect of nicotine on behavioral phenotypes and pathological characteristics of mice induced by human alpha-synuclein preformed fibers (-syn-PFF). MethodsMice were injected with 5 g of human -syn-PFF in the hippocampus while administering nicotine-containing drinking water (200g/mL). After 1 month, the motor ability, mood, spatial learning, and memory ability of the Parkinsons disease(PD)phenotype-like model were detected using open field, rotarod, Y maze, and O maze tests. The expression of pathological -syn, apoptotic proteins and the numbers of glial cells and neural stem cells in the hippocampus of mice were detected using western blotting and immunofluorescence. ResultsNicotine significantly reduced pathological -syn accumulation, -syn serine 129 phosphorylation and cell death caused by PFF injection in the hippocampus of mice, inhibited the increase of glial, microglia and apoptotic cells, decreased the expression levels of PI3K and Akt. ConclusionsNicotine may have inhibitory effects on human -syn-PFF-induced neuroinflammation and apoptosis. Thus, it reduces human -syn-PFF-induced behavioral deficits and pathological changes in mice.

Huntingtons disease (HD) is a neurodegenerative disease marked by progressive motor and non-motor symptoms such as neuropsychiatric disruption and cognitive dysfunction. It has been reported that some pathogenic mechanisms resulting in neuronal cell death in this disease involve neurodegeneration and oxidative stress. 3-Nitropropionic acid (3-NPA), a natural toxin that promotes the irreversible suppression of mitochondrial complex II, has been used to understand the HD pathogenesis. This neurotoxin mimics the biochemical, central neurodegeneration, peripheral and behavioral phenotype alterations observed in HD. Here we investigated 3-NPA (60 mg/kg) effects on histological and oxidative stress parameters on brain and muscular tissues. We also evaluated the effects of three antioxidant compounds on 3-NPA-induced behavioral phenotypes in adult zebrafish. For the evaluation of the antioxidant effects, adult zebrafish were submitted to a single acute intraperitoneal injection of vitamin C, creatine, or melatonin following 3-NPA chronic administration (60 mg/kg). 3-NPA treatment caused neurodegeneration, but did not alter the muscular tissue. 3-NPA neither change thiobarbituric acid reactive substances (TBARS) nor nonprotein thiol levels. Vitamin C and creatine treatments recovered the hypolocomotion induced by 3-NPA. Also, vitamin C and melatonin treatments improved the memory dysfunction caused by 3-NPA. Altogether, our findings showed that the 3-NPA induces neurodegeneration in adult zebrafish, and the vitamin C, creatine, and melatonin are beneficial in managing HD-like behavioral phenotypes. Thus, these antioxidants could be thought as complementary pharmacotherapies for the treatment of late-stage HD symptoms.

Some specific lipid molecules present in the brain are signaling molecules at the intracellular compartments or behaving as neurotransmitters or neuromodulators of other systems, binding to specific G protein-coupled receptors (GPCR) for neurolipids. One of these receptors is the sphingosine 1-phosphate receptor subtype 1, coupled to Gi/o-proteins and involved in cell proliferation, growth or neuroprotection. Thus, an interesting target for neurodegenerative diseases, such as Alzheimers. The present study compares the human cerebral distribution of the activity mediated by S1P1 receptor with the that in the brain of rodent experimental models, rat and mice by functional autoradiography, measuring the [35S]GTP{gamma}S binding stimulated by the S1P1 receptor selective agonist CYM-5442 to get the anatomy of the S1P1 receptor activity. The S1P1 receptor-mediated activity is, together with that of the CB1 cannabinoid receptor, one of the highest recorded for any GPCR in most of the grey matter areas of the brain, reaching up to 50%-500% over basal, depending on the agonist and brain area. The S1P1 receptor signaling is very relevant in those areas that regulate learning and memory processes, such as the basal forebrain, but also in others involved in control of motor processes or nociception e.g. basal ganglia. The results also reveal that the rat would be a preferable experimental model to extrapolate for the S1P1 receptor-mediated responses in human brain.

NLX-112 is a potent and selective 5-HT1A agonist that has successfully completed phase 2A clinical trial for treatment of L-DOPA-induced dyskinesia in Parkinsons disease (PD). We investigated the neuroprotective activity of NLX-112 in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Four groups of mice received either saline (1ml/kg) daily for 15 days, MPTP (21.4 mg/kg for 5 days, preceded and followed by 5 days saline, NLX-112 (1mg/kg/day for 15 days) or combined MPTP + NLX-112. Two weeks following cessation of treatments, NLX-112-treated mice showed increased locomotor activity and reduced anxiety-like behaviour in an open-field test, consistent with sustained effects of 5-HT1A receptor activation. MPTP-treated male mice showed a significant reduction of dopaminergic (i.e., tyrosine hydroxylase immunoreactive; TH-ir) neurones in the substantia nigra (SN) and the striatum by 40 and 55%, respectively. NLX-112 treatment elicited a significant protection against MPTP-induced loss of TH-ir neurones and nerve terminals. MPTP also a markedly increased the levels of GFAP-ir astrocytes and Iba1-ir microglia in the SN, and co-expression of glial-derived neurotrophic factor (GDNF) in the GFAP-ir astrocytes in both the SN and the striatum. However, in MPTP treated mice, NLX-112, markedly reversed microglial expression in the SN, and upregulated GFAP/GDNF co-localisation in both the striatum and the SN. Overall, the present study demonstrates a robust neuroprotective effect of NLX-112 in a mouse model of PD by preventing microgliosis, upregulating GDNF and favouring sustained pro-locomotor activity.

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single toxic dose of the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, seven days of repeated intranasal administration of gangliosides GM1 or GD3 24 hours after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 can prevent the organophosphate-related alterations in those brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological deficits associated with a class of poisons that endangers millions of people worldwide. Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646417v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@edf17dorg.highwire.dtl.DTLVardef@1895982org.highwire.dtl.DTLVardef@538e99org.highwire.dtl.DTLVardef@1b700d3_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIA single exposure to DFP, which causes cognitive deficits, dysregulates NGF and BDNF signaling C_LIO_LIGM1 or GD3 24 hours after DFP injection prevents the alteration of the neurotrophin signaling C_LIO_LIIntranasal ganglioside treatment provides neuroprotective effects against persistent organophosphate toxicity C_LI

Manganism, a disease with characteristic degeneration of dopamine neurons, has distinct aetiology and clinical manifestations, striking similarities with Parkinsons Disease (PD). Environmental exposure to manganese (Mn) is one of the risk factors for the occurrence of PD. The definitive role of dopamine (DA) in Mn mediated neurodegeneration, and its developmental impact has not been well studied. To understand the pathways involved in Mn-induced neurotoxicity, we used C. elegans as the model system. Our results showed that adult worms treated with 50 and 100 mM MnCl2 significantly increased DA neurodegeneration. L1 larvae spared without neurodegeneration when treated with MnCl2 alone showed a significant increase in neurodegeneration (>50%) when MnCl2 exposure was given after DA pretreatment. However, both adult and larval exposure to MnCl2 demonstrated significant toxicity by reducing the survival rate. In adult worms, 100 mM MnCl2 treatment after DA pretreatment further elevated the percentage of neurodegeneration. The Mn or DA alone exposed adult worms showed recovery of neuronal dopamine function within 24 hours, although exogenous DA and Mn treated worms showed prolonged behavioural defects. Cat-2 mutants, without DA, were resistant to Mn mediated neurodegeneration. In contrast, Cat-2 overexpressing strain displayed severe neurodegeneration at lower concentrations of MnCl2 (50 mM). Our results on biochemical, behavioural and genetic assays proved endogenous/exogenous DA level controls the sensitivity to Mn induced dopaminergic neurotoxicity.

Maternal separation during early life is a well-established model for inducing neurodevelopmental impairments. Mechanical stimulation by passive movement, such as three-dimensional orbital shaking (3D-OS), has been suggested as a neuroprotective intervention in cell and tissue models, but its effects in neonatal animals remain unknown. We investigated whether 3D-OS applied during the postnatal period could attenuate neurogenesis impairments and cognitive deficits induced by maternal separation in rats. Eighteen newborn Sprague Dawley rats were assigned to control (C), maternal separation (MS), or maternal separation plus orbital shaking (MSOS) groups. Maternal separation was performed 3 h/day between postnatal days 2-21; MSOS additionally received 3D-OS stimulation (25 rpm, 3 h/day). Behavioural tests (Open Field, Novel Object Recognition, Morris Water Maze, Passive Avoidance), combined with RT-qPCR, Western blot, histology, and immunohistochemistry were conducted. MSOS rats displayed improved spatial learning in the early phases of the Morris Water Maze and recovered retention memory in Passive Avoidance compared to MS. In contrast, Open Field and Novel Object Recognition tests revealed no differences, and Western blot did not detect significant protein changes. Histological analysis showed reduced neuronal loss and vacuolisation in hippocampal and cortical regions of MSOS rats. RT-qPCR demonstrated reduced hippocampal FGF2 and FGFR1 expression in MS, partially restored by 3D-OS, while immunohistochemistry indicated increased FGFR2 and decreased FGFR1 in MSOS. Early-life 3D-OS administration alleviated maternal separation-induced cognitive decline and structural impairments, and enhanced hippocampal plasticity markers, providing preclinical evidence that moderate mechanical stimulation may support brain development and exert neuroprotective effects against early-life stress. HighlightsO_LIEarly-life 3D-OS mitigated maternal separation-induced deficits. C_LIO_LIImproved performance in Morris Water Maze and Passive Avoidance tasks. C_LIO_LINo significant effects observed in OFT, NOR, or Western blot. C_LIO_LI3D-OS restored hippocampal FGF-2 and FGFR1 mRNA levels in stressed rats. C_LIO_LIGentle mechanical stimulation may support early brain development. C_LI

Low toxic doses of tramadol induced animal brain cortex apoptosis and hippocampus injury. Adding nicotine reverted hippocampus pathological changes without triggering brain injury. The expression of CHOP protein in real-time PCR showed mild Endoplasmic reticulum stress (ER) in rats brains. Histological, immunohistochemical, and western blotting analysis of CHOP and BIP chaperones demonstrated Endoplasmic reticulum stress in brain and liver tissue samples. Furthermore, the levels of apoptosis and autophagy markers demonstrated a mild increase. Adding Nicotine relatively decreasedbrain and liver ER stress. The combined profile was considerably protective in comparison to administering each drug separately. Mild ER stress is essential for normal cell functions. The blood level of serotonin was high in all study groups with a marked increase in its level when tramadol and nicotine were combined. Low toxic doses of tramadol in combination with nicotine were safe at the reproductive system level which was evaluated by histological examination and animal blood androgen assay. Generally, combining low-dose tramadol with smoking was found to be safe in various animal tissues and organs, however, the high serotonin level in the blood can be critical and associated with a high risk of serious withdrawal and pathological consequences. Serotonin receptor blockers such as olanzapine may increase systemic serotonin levels and need further investigation to utterly pinpoint their roles in managing mood disorders.

BackgroundCyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme involved in neuronal development, maturation and survival. CDK5 activity is tightly regulated by association with regulatory proteins p35 and p39. Upon neuronal insults, increased intracellular calcium activates calpain, cleaving p35 into p25, which has a higher affinity for CDK5. p25 hyperactivates CDK5, initiating apoptotic cascades that lead to significant dopaminergic (DAergic) loss that can leads to neurodegenerative disorders, such as Parkinsons disease (PD). ObjectiveThis study investigates hyperactivation of CDK5/p25 in the 6-hydroxydopamine (6-OHDA) rat model of PD and specific inhibition of CDK5/p25 by truncated peptide 5 (TP5). TP5 was investigated for amelioration of 6-OHDA induced behaviour impairments and significant protection of dopamine neurons through tyrosine hydroxylase (TH). Methods6-OHDA induced motor impairments and reduced TH. Motor assessments included locomotor activity, beam transversal, fixed speed rotarod and amphetamine-induced rotations. Immunohistochemistry investigated DAergic neurodegeneration using TH levels and immunoprecipitation and assay investigated CDK5 activity. ResultsPre-administration of TP5 maintained locomotor activity, preserved beam transversal scores, protected motor coordination and attenuated amphetamine induced rotations in 6-OHDA lesioned rats, all indicative of neuroprotection by TP5. 6-OHDA without pretreatment of TP increased CDK5 activation. CDK5 activity in TP5+6-OHDA animals was not significantly different from artificial cerebrospinal fluid (aCSF) treated sham surgery controls. Immunohistochemistry revealed significant TH protection within the substantia nigra (SN) of TP5 pretreated animals. Conclusions6-OHDA increases CDK5 activity. Hyperactive CDK5/p25 inhibition in the 6-OHDA model has neuroprotective capability, protecting against the development of a toxin-based induction of PD-like motor phenotypes and pathology. This supports CDK5/p25 specific inhibition as a target for further neuroprotective therapeutic development.

Alcoholism is one of the oldest and most widespread drug addictions described in the literature and one of the biggest concerns in the health area. There is a growing number of investigations into the medical, social, and economic problems triggered by the abusive consumption of ethanol-based distillates or fermented products that can affect tissues or organs in different ways. Intrinsic or extrinsic situations that threaten organic homeostasis trigger a series of adaptive responses that constitute the stress systems, which consist of different physical and mental reactions that oppose the stressful stimulus, aiming to restore the lost balance. The UChA and UChB rat varieties constitute rare models for studies related to the genetic, biochemical, physiological, nutritional and pharmacological factors of the effects of alcohol, as well as appetite and tolerance, important factors related to human alcoholism. The present work arose from the interest in investigating the effects of stress on these animals, since several aspects of alcoholism may be the result of stress experienced early in life, being potentiated or not in the adult individual. Thus, the research proposes to investigate and evaluate whether maternal neonatal separation, applied to male offspring of UChA and UChB rats, potentiates the toxic effects of chronic alcohol intake on choroid plexus cells. Maternal separation (MS) change the ethanol consumption and not altered IGF-I expressions. There was a negative association between ethanol consumption and MS in body mass gain and other correlations with feed, water consumptions and hormones dosages. Maternal separation potentiated epithelial atrophy of the choroid plexus in UChA and UChB animals.

BackgroundMotor coordination (MC) and long-term recognition memory (LRM) are affected in people with multiple sclerosis (MS). The exact mechanism underlying the pathogenesis of MS is still unknown. However, oxidative stress is one of the underlying mechanisms of the pathogenesis of MS that is detrimental to myelin due to an imbalance in the levels of antioxidants. Dimethyl fumarate (DMF) is a first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Since OS plays a significant role in MS, in addition to DMF treatment, inhibition of NADPH oxidases (NOXs) may provide surplus glutathione (GSH) to prevent myelin loss. Hence, the objective of this study was to test the effect of a fixed dose of apocynin (50 mg/kg) combined with a fixed-dose DMF (30 mg/kg) on antioxidants, MC, and LRM in cuprizone (CUP)-induced mice model of demyelination. MethodsThe MC and LRM were evaluated by narrow beam and novel object recognition tests, catalase and superoxide dismutase activity by the degradation of hydrogen peroxide and nitroblue tetrazolium method; malondialdehyde by thiobarbituric acid assay, GSH by high-performance liquid chromatography, and presence of myelin by modified luxol fast blue staining. ResultsThe combination therapy with DMF plus APO in CUP-fed mice preserved LRM and MC with a significant increase in catalase activity (1.15 {+/-} 0.04 U/mg protein; p<0.001), superoxide dismutase activity (9.25 {+/-} 0.10 U/mg protein; p<0.0001), and GSH (195.25 {+/-} 22.75 nmol/mg protein, ****p<0.0001) of the cerebral cortex versus disease control (98.52 {+/-} 8.85 nmol/mg protein). APO plus DMF30 in CUP-fed mice also preserved myelin (p<0.001) at the corpus callosum of mice brains. ConclusionsWe conclude that APO combination with DMF might have protected myelin by modulating (increasing) the levels of antioxidants to act against CUP-induced oxidative stress and thereby preserved MC and LRM in the cuprizone-induced mice model of demyelination.

BackgroundChronic methamphetamine abuse leads to cognitive decline, posing a significant threat to human health and contributing to loss of productivity. However, the intricate and multifaceted mechanisms underlying methamphetamine-induced neurotoxicity have impeded the development of effective therapeutic interventions. MethodsTo establish a mouse model of cognitive decline induced by chronic methamphetamine exposure, we employed a large sample size and conducted two behavioral tests (Y-maze and novel object recognition test) at 2 and 4 weeks post-exposure. Subsequently, single-cell RNA sequencing was utilized to delineate the mRNA expression profiles of individual cells within the hippocampus. Comprehensive bioinformatics analyses, including cell clustering and identification, differential gene expression analysis, cellular communication analysis, pseudotemporal trajectory analysis, and transcription factor regulation analysis, were performed to elucidate the cellular-level changes in mRNA profiles caused by chronic methamphetamine exposure. ResultsOur findings demonstrated impairments in working memory, spatial cognition, learning, and cognitive memory. After 4 weeks of behavioral testing, we identified diverse cell types in the hippocampi of METH- and saline-treated mice through scRNA-seq, including glial cells, stromal cells, vascular cells, and immune cells. We observed that methamphetamine exerts cell-specific effects on gene expression changes associated with neuroinflammation, blood-brain barrier disruption, neuronal support dysfunction, and immune dysregulation. Furthermore, cross-talk analysis revealed extensive alterations in cellular communication patterns and signal changes within the hippocampal microenvironment induced by methamphetamine exposure. Pseudotime analysis predicted hippocampal neurogenesis disorders and identified key regulatory genes implicated in chronic methamphetamine abuse. Transcription factor analysis uncovered regulators and pathways linked to astrocyte-mediated neuroinflammation, endothelial junction integrity, microglial synaptic remodeling, and oligodendrocyte-supported neuronal cell bodies and axons. Additionally, it highlighted the role of neural precursor cells in various forms of neurodegeneration. ConclusionsThis study establishes a robust mouse model of cognitive impairment induced by chronic methamphetamine exposure. It provides valuable biological insights, characterizes the single-cell atlas of the hippocampus, and offers novel directions for investigating neurological damage associated with chronic methamphetamine-induced cognitive decline.

Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kg i.p. ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.

It is established that p-cresol, a compound produced by bacterial colonies within the gastrointestinal tract of mammals, plays a contributory role in the manifestation of various mental disorders. Recently, our research demonstrated that diminishing p-cresol levels in the brain adversely impact the behavioral manifestation of cognitive abilities in rats. In this study, we aimed to investigate the impact of augmenting p-cresol levels in the brain on learning. The Active Avoidance Test was employed to assess learning capabilities. The results, with a high level of confidence, indicated that rats with an increased concentration of p-cresol in the brain exhibited superior task performance and accelerated learning compared to the control group.

BackgroundAyahuasca, a psychoactive Amazonian preparation, is increasingly studied for substance-use disorders. ObjectivesInvestigate whether oral lyophilised-ayahuasca attenuates ethanol-induced conditioned place preference (CPP) in mice and alters {Delta}FosB expression in nucleus accumbens (NAc). MethodsMale Swiss mice received water or ayahuasca (130-1950 mg/kg, p.o.) 30 min before each of eight ethanol pairings (2g/kg i.p.) in a CPP paradigm. A separate cohort underwent acute toxicology (650-5000mg/kg) with behavioural-observation and rotarod. Alkaloids were quantified by LC-MS/MS. {Delta}FosB-immunoreactive nuclei were counted in NAc 24h after the CPP post-test. ResultsAlkaloids levels were within traditional ranges. High-dose ayahuasca(5000 mg/kg) produced transient-serotonergic-syndrome-like signs and rotarod locomotor-deficit; lower doses did not express toxicity. Ethanol produced a moderate-CPP in controls({Delta}Time{approx}+60s), whereas ayahuasca-pretreatment abolished preference at all doses({Delta}Time within{+/-}7s). One-way ANOVA on {Delta}Time showed a robust-Treatment effect(F(3,36)=8.83, p=0.00016); Tukey tests: control differed from each ayahuasca group (all p<0.05), with no differences among ayahuasca doses. {Delta}FosB density did not differ among groups(p>0.05). ConclusionsAyahuasca was well tolerated at ceremonies-equivalent doses and blocked ethanol-induced-CPP across all doses, while {Delta}FosB levels in NAc were unchanged at 24h. Limitations on the CPP baseline and {Delta}FosB results may limit sensitivity, generalisability and interpretation. Findings provide preliminary evidence that ayahuasca-pretreatment may blunt ethanol-context preference, reinforcing the need of replication with stronger reward baselines, naive controls and complementary molecular markers.

The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2 improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine, in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 prevented this deleterious effect in spatial memory when evaluated in spatial Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of CB1 receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.

Alzheimers disease (AD) is a type of dementia that affects millions of people. Although there is no cure, several study strategies seek to elucidate the mechanisms of the disease. Recent studies address the benefits of taurine. Thus, the present study aims to analyze the neuroprotective effect of taurine on human neuroblastoma, using an in vitro experimental model of oxidative stress induced by hydrocortisone in the SH-SY5Y cell line as a characteristic model of AD. The violet crystal assay was used for cell viability and the evaluation of cell morphology was performed by scanning electron microscopy (SEM). After pretreatment with taurine, the SH-SY5Y cell showed an improvement in cell viability in the face of oxidative stress and improved cell morphology. Thus, the treatment presented a neuroprotective effect. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/441504v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@12dcb58org.highwire.dtl.DTLVardef@1810110org.highwire.dtl.DTLVardef@6cc235org.highwire.dtl.DTLVardef@424491_HPS_FORMAT_FIGEXP M_FIG C_FIG

Oxidative stress is believed to play a significant role in the pathophysiology of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. The present study aims to firstly investigate the antioxidant activities of EPI-589, a small-molecule quinone derivative, under cell-free or cell culture conditions, and explore the in vivo efficacy of EPI-589 in the wobbler mouse model of human motor neuron disease. The reduced form of EPI-589 showed hydroxyl radical scavenging activities, whereas the oxidized form i.e. EPI-589 did not. In cellular models utilizing ALS patient-derived fibroblasts carrying mutations in the fused in sarcoma (FUS) gene or superoxide dismutase 1 (SOD1) gene, EPI-589 potently protected cells from oxidative stress induced by buthionine sulfoximine and ferric citrate. Protective effect of EPI-589 was also observed in culture of mouse immortalized striatal STHdHQ7/Q7 cells with cystine deprivation. In wobbler mice, oral administration of dietary EPI-589 provided long-lasting amelioration of both of deterioration of the rotarod walking performance and progression of forelimb deformity in wobbler mice throughout the treatment. In separate studies, we found that EPI-589 significantly suppressed changes of pathophysiological markers such as plasma phosphorylated neurofilament heavy chain, urinary 8-hydroxy-2-deoxyguanosine, and cervical N-acetylaspartate in untreated wobbler mice. Thus, the present study firstly demonstrates that EPI-589 is a highly potent, redox-active neuroprotectant and robustly delays the symptomatic and pathophysiological progression of motor neuron disease in the wobbler mouse, and these findings strongly encourage further exploration of the therapeutic potential of EPI-589 for the treatment of ALS.

BackgroundGestational protein intake restriction induces long-lasting harmful outcomes in the offsprings organs and systems. AimsThis study sought to evaluate the effects of protein restriction during pregnancy and breastfeeding in 42-day-old male offspring on the structure of the hippocampus, behavior tests related to memory and emotions, and the influence of an enriched environment on these parameters. Results and DiscussionThe current study demonstrated that maternal protein restriction during neural development causes crucial morphological changes in the hippocampus, making the LP offspring vulnerable to specific neural disorders in adulthood. In addition, it supports the selfish brain theory, a paradigm that postulates the brain maintains its mass selfishly by reallocating resources from other body parts when faced with nutritional stress. However, the hippocampus cellularity pattern was profoundly altered, significantly reducing the number of neurons after the breastfeeding period. This may expand the understanding of nutritional stress affecting the brain areas constitution and its supposed effects on posterior behavioral disorders. Here, reciprocal data was observed between brain masses, changes in the hippocampus cell pattern, and decreased body mass in the LP progeny. In conclusion it was demonstrated that neuronal composition and structure profoundly modified by dietary restriction are surprisingly restored from primordial cells by exposure to the enriched environment. In addition, we must emphasize that although we have observed a significant reduction in the number of neurons after gestational and breastfeeding periods, we demonstrated for the first time a substantial reduction in the fear-reflecting behavior, which an enriched environment exposure may revert. The enriched environment also significantly modified the discrimination ratio, increasing the ability of both progenies to discriminate between novel and familiar objects in a short time associated with reverse abnormal hippocampus cell patterns. These findings underscore the potential for environmental interventions to mitigate the effects of early=life nutritional stress on brain development and behavior.

Diabetes Mellitus (DM) is a rapidly increasing disease around the world. It is known that DM is associated with numerous complications which affect life quality by its debilitating nature. DM is associated with cognitive impairment and neurodegeneration, partly driven by neuroinflammation and disrupted neuronal signalling. Incretin-based treatments have recently been suggested to exert potential effects on the central nervous system in diabetic patients. However, the triple agonist of GIP/GLP-1/GCG Retatrutides effects on cognition under diabetic conditions remain unexplored. This study aims to reveal whether impaired cognitive performance, such as learning and memory, is ameliorated by Retatrutide treatment in diabetic rats, together with associated metabolic, inflammatory and histological changes. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic rats treated with Retatrutide (STZR), and sham rats treated with Retatrutide alone (R). DM was induced by streptozotocin injections. Spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while neuroinflammatory markers (IL-1{beta}, TNF-), neurotrophic-related gene expression (BDNF, CREB, AKT), Tau protein levels, and histopathological changes in the cortex and hippocampus were evaluated using molecular, biochemical, and histological analyses. Streptozotocin-induced diabetes resulted in persistent hyperglycaemia, total body weight loss, impaired learning and memory. Retatrutide treatment reduced blood glucose levels without achieving a full euglycaemia or preventing weight loss. Behavioural tests showed that Retatrutide treatment preserved spatial learning and short-term memory compared to untreated animals. These effects were accompanied by attenuation of neuroinflammatory responses, particularly reduced TNF- levels, trends toward preserved neurotrophic-related transcriptional profiles, and partial maintenance of cortical and hippocampal structural integrity. Retatrutide alone did not enhance cognitive performance beyond control levels. These findings support the hypothesis that triple agonists may exert beneficial effects on cognitive performance under diabetic conditions. Retatrutide alleviates DM-associated cognitive impairment in streptozotocin-induced diabetic rats and is associated with reduced neural inflammatory burden and protected neuroanatomical structure. The observed cognitive benefits appear to extend beyond metabolic regulation alone. Further studies in models more closely reflecting type 2 diabetes are warranted to clarify the underlying mechanisms and translational relevance.