Neurotoxicity Research最新文献

The global rise in obesity and overweight over the past few decades has led to numerous associated disorders, including cognitive deficits. This study evaluate investigates the effects of Naringin (Nar) on memory and learning, anxiety-like behaviors, brain-derived neurotrophic factor (BDNF), cAMP responsive element binding protein (CREB), acetylcholinesterase (AChE) activity, and neuronal density in the CA₁/CA₃ subfields of the hippocampus in an MSG-induced obese obesity rat model. Forty-eight male Wistar rat pups were randomly divided into four groups: Control, MSG, MSG + Nar50, and MSG + Nar100. MSG (4 g/kg BW) was administered subcutaneously in the cervical region from PND 2 to PND10, while Nar (50 mg/kg BW and 100 mg/kg BW) was administered orally from PND30 to PND42. After the treatment period, cognitive (working memory and passive avoidance) and anxiety-related tests (elevated plus maze and novelty-suppressed feeding test) were performed. Subsequently, hippocampal protein level of BDNF and CREB/BDNF gene expression, AChE activity and neuronal density in the CA₁ and CA₃ regions of the hippocampus were measured. Relative to the MSG group, the Nar-treated rats demonstrated improvements in spatial working memory, reduced anxiety-related behaviors, elevated hippocampal CREB and BDNF genes and BDNF protein levels, and reduced AChE activity. Additionally, Nar treatment increased neuronal density in the CA₁/CA₃ subfields of the hippocampus. These findings suggest that Nar enhances cognitive function and mitigates anxiety in MSG-induced obese rats by modulating CREB/BDNF signaling pathway, inhibiting AChE, and exerting neuroprotective effects in the hippocampus.

Early parental care is critical for the development of cortico-limbic circuits regulating stress responses and emotional well-being. Conversely, infant maltreatment can increase susceptibility to mood disorders-such as anxiety and depression-and impair stress-coping abilities. Here, we employed the Scarcity-Adversity Model (SAM) in rats, limiting nesting resources from postnatal days 8-12, to examine its effects on maternal and adult offspring behavior. SAM-exposed mothers exhibited fragmented care and increased violence towards pups. By postpartum day (PPD) 13, maternal fecal corticosterone metabolites (FCM) were elevated, indicating heightened stress. At weaning, SAM dams also showed increased anxiety-like behavior in the Elevated Plus Maze (EPM), suggesting significant emotional alterations. In adulthood, SAM-exposed offspring underwent anxiogenic tests. Both male and female SAM offspring showed increased latency to enter open arms and reduced risk-assessment in the EPM, though females displayed anxiolytic-like behavior in the Light-Dark Box. Male SAM rats had reduced locomotion in the Open Field, earlier onset and increased immobility in the Forced Swim, and increased latency to groom in the Sucrose Splash. When exposed to acute stress, male SAM rats had lower FCM levels, consistent with their passive stress reactivity. These findings confirm SAM induces long-lasting, sex-specific changes in risk-taking, novelty responsiveness, and stress reactions, underscoring the importance of early nurturing in promoting well-being and reducing psychopathological risk.

Dopamine (DA) has long been considered a major factor in the development of Parkinson's disease (PD). Ethanol (EtOH) and nicotine (Nic), either alone or in combination, have been shown to affect nigrostriatal dopaminergic neuronal activity. Here, we investigate whether EtOH and Nic alone or in co-exposure can restore the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine (DA), DA metabolites, and tyrosine hydroxylase (TH) in the striatum and hippocampus of C57BL/6N mice. MPTP-treated mice were treated intraperitoneally with saline (control), EtOH (1.0-3.0 g/kg), Nic (0.5-2.0 mg/kg), or a combination of EtOH and Nic. Brain samples were collected 1 h after treatment. DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were measured by HPLC-ECD, while TH protein content and TH phosphorylation at Ser31 (pSer31 TH) were quantified by Western blot. EtOH (2.0 and 3.0 g/kg) alone reversed the effects of MPTP treatment in both studied brain regions, as evidenced by an increase in DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to the MPTP group, indicating restorative effects on DA neurons in the MPTP model. Likewise, Nic (1.0 and 2.0 mg/kg) alone reversed MPTP treatment effects, with treated mice showing increased DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to MPTP mice. Co-administration of EtOH (2.0 g/kg) and Nic (1.0 mg/kg) further increased DA, DOPAC and HVA tissue contents, TH protein, and pSer31 TH, indicating an additive effect. These results show that moderate to high doses of EtOH and Nic induce similar increases in brain DA and TH via TH phosphorylation activation in MPTP model mice. EtOH and Nic showed an additive effect in combination, suggesting that their co-application could be a potent therapeutic strategy for treating PD.

Tau is a neuronal protein that confers stability to microtubules; however, its hyperphosphorylation and accumulation can lead to an impairment of protein degradation pathways, such as autophagy. Autophagy is a lysosomal catabolic process responsible for degrading cytosolic components, being essential for cellular homeostasis and survival. In this context, autophagy modulation has been postulated as a possible therapeutic target for the treatment of neurodegenerative diseases. Studies point to the modulatory and neuroprotective role of the cannabinoid system in neurodegenerative models and here it was investigated the effects of cannabidiol (CBD) on autophagy in a human neuroblastoma strain (SH-SY5Y) that overexpresses the EGFP-Tau WT (Wild Type) protein in an inducible Tet-On system way. The results demonstrated that CBD (100 nM and 10 µM) decreased the expression of AT8 and total tau proteins, activating autophagy, evidenced by increased expression of light chain 3-II (LC3-II) protein and formation of autophagosomes. Furthermore, the cannabinoid compounds CBD, ACEA (CB1 agonist) and GW-405,833 (CB2 agonist) decreased the fluorescence intensity of EGFP-Tau WT; and when chloroquine, an autophagic blocker, was used, there was a reversal in the fluorescence intensity of EGFP-Tau WT with CBD (1 and 10 µM) and GW-405,833 (2 µM), demonstrating the possible participation of autophagy in these groups. Thus, it was possible to conclude that CBD induced autophagy in EGFP-Tau WT cells which increased tau degradation, showing its possible neuroprotective role. Hence, this study may contribute to a better understanding of how cannabinoids can modulate autophagy and present a potential therapeutic target in a neurodegeneration model.

Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.

Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25 mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5 mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15 mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25 mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

To identify factors involved in methamphetamine (METH) neurotoxicity, we comprehensively searched for genes which were differentially expressed in mouse striatum after METH administration using differential display (DD) reverse transcription-PCR method and sequent single-strand conformation polymorphism analysis, and found two DD cDNA fragments later identified as mRNA of Nedd4 (neural precursor cell expressed developmentally downregulated 4) WW domain-binding protein 5 (N4WBP5), later named Nedd4 family-interacting protein 1 (Ndfip1). It is an adaptor protein for the binding between Nedd4 of ubiquitin ligase (E3) and target substrate protein for ubiquitination. Northern blot analysis confirmed drastic increases in Ndfip1 mRNA in the striatum after METH injections, and in situ hybridization histochemistry showed that the mRNA expression was increased in the hippocampus and cerebellum at 2 h-2 days, in the cerebral cortex and striatum at 18 h-2 days after single METH administration. The knockdown of Ndfip1 expression with Ndfip1 siRNA significantly aggravated METH-induced neurotoxicity in the cultured monoaminergic neuronal cells. These results suggest that drastic increases in Ndfip1 mRNA is compensatory reaction to protect neurons against METH-induced neurotoxicity.

Mitochondria produces energy through oxidative phosphorylation (OXPHOS), maintaining calcium homeostasis, survival/death cell signaling mechanisms, and redox balance. These mitochondrial functions are especially critical for neurons. The hippocampus is crucial for memory formation in the brain, which is a process with high mitochondrial function demand. Loss of hippocampal function in aging is related to neuronal damage, where mitochondrial impairment is critical. Synaptic and mitochondrial dysfunction are early events in aging; both are regulated reciprocally and contribute to age-associated memory loss together. We previously showed that prolonged treatment with Curcumin or Mitoquinone (MitoQ) improves mitochondrial functions in aged mice, exerting similar neuroprotective effects. Curcumin has been described as an anti-inflammatory and antioxidant compound, and MitoQ is a potent antioxidant directly targeting mitochondria; however, whether Curcumin exerts a direct impact on the mitochondria is unclear. In this work, we study whether Curcumin could have a mechanism similar to MitoQ targeting the mitochondria. We utilized hippocampal slices of 4-6-month-old C57BL6 mice to assess the cellular changes induced by acute Curcumin treatment ex-vivo compared to MitoQ. Our results strongly suggest that both compounds improve the synaptic structure, oxidative state, and energy production in the hippocampus. Nevertheless, Curcumin and MitoQ modify mitochondrial function differently; MitoQ improves the mitochondrial bioenergetics state, reducing ROS production and increasing ATP generation. In contrast, Curcumin reduces mitochondrial calcium levels and prevents calcium overload related to mitochondrial swelling. Thus, Curcumin is described as a new regulator of mitochondrial calcium homeostasis and could be used in pathological events involving calcium deregulation and excitotoxicity, such as aging and neurodegenerative diseases.

Chronic use of typical antipsychotics can lead to varying motor effects depending on the timing of analysis. Acute treatment typically induces hypokinesia, resembling parkinsonism, while repeated use can result in tardive dyskinesia, a hyperkinetic syndrome marked by involuntary orofacial movements, such as vacuous chewing movements in mice. Tardive dyskinesia is particularly concerning due to its potential irreversibility and associated motor discomfort. One prevailing theory suggests that tardive dyskinesia arises from hypersensitivity of D2-type dopaminergic receptors caused by continuous blockade from typical antipsychotics like haloperidol. Additionally, increased inflammation, oxidative stress, and elevated FosB protein expression in the dorsolateral striatum are implicated in its pathophysiology. Current treatments for tardive dyskinesia often lack clear efficacy and may lead to significant side effects. Cannabigerol, a non-psychotomimetic cannabinoid with antioxidant and anti-inflammatory properties, has been investigated for its potential antidyskinetic effects. In this study, mice were treated with cannabigerol at doses of 3 and 10 mg/kg to evaluate its ability to prevent, ameliorate, or reverse haloperidol-induced vacuous chewing movements. Cannabigerol successfully reduced vacuous chewing movements without affecting normal motor activity, exacerbating haloperidol-induced hypokinesia, or inducing dyskinetic effects on its own. However, no significant reversal of the haloperidol-induced motor effects was observed under the current protocol. Furthermore, cannabigerol did not alter FosB expression or microglia morphology. These findings underscore the need for further research to explore cannabigerol's therapeutic potential and contribute to our understanding of its possible clinical applications in managing tardive dyskinesia.