RESUMO
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Assuntos
Astrócitos , Transtornos da Memória , Metanfetamina , Microglia , Minociclina , Memória Espacial , Animais , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Transtornos da Memória/induzido quimicamente , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos , Masculino , Minociclina/farmacologia , Camundongos Endogâmicos C57BL , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Estimulantes do Sistema Nervoso Central/toxicidadeRESUMO
Methamphetamine (Meth) use is known to induce complex neuroinflammatory responses, particularly involving astrocytes and microglia. Building upon our previous research, which demonstrated that Meth stimulates astrocytes to release tumor necrosis factor (TNF) and glutamate, leading to microglial activation, this study investigates the role of the anti-inflammatory cytokine interleukin-10 (IL-10) in this process. Our findings reveal that the presence of recombinant IL-10 (rIL-10) counteracts Meth-induced excessive glutamate release in astrocyte cultures, which significantly reduces microglial activation. This reduction is associated with the modulation of astrocytic intracellular calcium (Ca2+) dynamics, particularly by restricting the release of Ca2+ from the endoplasmic reticulum to the cytoplasm. Furthermore, we identify the small Rho GTPase Cdc42 as a crucial intermediary in the astrocyte-to-microglia communication pathway under Meth exposure. By employing a transgenic mouse model that overexpresses IL-10 (pMT-10), we also demonstrate in vivo that IL-10 prevents Meth-induced neuroinflammation. These findings not only enhance our understanding of Meth-related neuroinflammatory mechanisms, but also suggest IL-10 and Cdc42 as putative therapeutic targets for treating Meth-induced neuroinflammation.
Assuntos
Astrócitos , Interleucina-10 , Metanfetamina , Camundongos Transgênicos , Microglia , Proteína cdc42 de Ligação ao GTP , Animais , Metanfetamina/toxicidade , Metanfetamina/farmacologia , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Proteína cdc42 de Ligação ao GTP/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estimulantes do Sistema Nervoso Central/toxicidade , Estimulantes do Sistema Nervoso Central/farmacologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Células Cultivadas , Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidadeRESUMO
Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.
Assuntos
Estimulantes do Sistema Nervoso Central , Dimesilato de Lisdexanfetamina , Humanos , Adulto , Criança , Adolescente , Masculino , Ratos , Animais , Dimesilato de Lisdexanfetamina/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Dextroanfetamina/toxicidade , Dextroanfetamina/uso terapêutico , Resultado do Tratamento , Ratos Wistar , SêmenRESUMO
Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest that METH can disrupt the gut microbiota. Furthermore, the gut-testis axis concept has gained attention due to the potential link between gut microbiome dysfunction and reproductive health. Nonetheless, the role of the gut microbiota in mediating the impact of METH on male reproductive toxicity remains unclear. In this study, we employed a mouse model exposed to escalating doses of METH to assess sperm quality, testicular pathology, and reproductive hormone levels. The fecal microbiota transplantation method was employed to investigate the effect of gut microbiota on male reproductive toxicity. Transcriptomic, metabolomic, and microbiological analyses were conducted to explore the damage mechanism to the male reproductive system caused by METH. We found that METH exposure led to hormonal disorders, decreased sperm quality, and changes in the gut microbiota and testicular metabolome in mice. Testicular RNA sequencing revealed enrichment of several Gene Ontology terms associated with reproductive processes, as well as PI3K-Akt signaling pathways. FMT conveyed similar reproductive damage from METH-treated mice to healthy recipient mice. The aforementioned findings suggest that the gut microbiota plays a substantial role in facilitating the reproductive toxicity caused by METH, thereby highlighting a prospective avenue for therapeutic intervention in the context of METH-induced infertility.
Assuntos
Microbioma Gastrointestinal , Metanfetamina , Reprodução , Testículo , Animais , Metanfetamina/toxicidade , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Testículo/efeitos dos fármacos , Testículo/patologia , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estimulantes do Sistema Nervoso Central/toxicidade , Transplante de Microbiota FecalRESUMO
Amphetamine-type stimulants are abused worldwide, and methamphetamine (METH) accounts for a large majority of seized abused drug cases. Recently, the paternal origin of health and disease theory has been proposed as a concept wherein paternal factors influence descendants. Although METH abuse is more common among males, its effects on their descendants were not examined. Therefore, we investigated the effects of paternal METH exposure on F1 and F2 levels in a mouse model. Sires were administered METH for 21 days and mated with female mice to obtain F1 mice. Growth evaluations (number of births, survival rate, body weight, righting reflex, cliff avoidance tests, and wire-hanging maneuver) were performed on F1 mice. Upon reaching six weeks of age, the mice were subjected to spontaneous locomotion, elevated plus-maze, acute METH treatment, and passive avoidance tests. Additionally, RNA-seq was performed on the striatum of male mice. Male F1 mice were mated with female mice to obtain F2 mice. They were subjected to the same tests as the F1 mice. Paternal METH exposure resulted in delayed growth and decreased memory function in F1 mice, overweight in F2 mice, decreased METH sensitivity, and reduced anxiety-related behaviors in female F2 mice. Enrichment analysis revealed significant enrichment of terms related to behavior in F1 and protein folding in F2. These results indicated that the effects of paternal METH exposure vary across generations. The effects of paternal factors need to be examined not only in F1, but also in F2 and beyond.
Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Feminino , Masculino , Animais , Camundongos , Metanfetamina/toxicidade , Anfetamina , Estimulantes do Sistema Nervoso Central/toxicidade , Peso Corporal , Corpo EstriadoRESUMO
OBJECTIVE: The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high-dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. MATERIALS AND METHODS: A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9-20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10 mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10 mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti-GFAP, and antisynaptophysin staining methods. RESULTS: While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8-10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. CONCLUSION: It is concluded that high-dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects.
Assuntos
Cafeína , Hipocampo , Melatonina , Fármacos Neuroprotetores , Ratos Wistar , Animais , Feminino , Melatonina/farmacologia , Melatonina/administração & dosagem , Hipocampo/efeitos dos fármacos , Gravidez , Cafeína/administração & dosagem , Cafeína/farmacologia , Ratos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Estimulantes do Sistema Nervoso Central/toxicidade , Estimulantes do Sistema Nervoso Central/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
This study represents the first application of in silico methods to evaluate the toxicity of 4-methylphenidate (4-Mmph), a new psychoactive substance (NPS). Using advanced in silico toxicology tools, it was feasible to anticipate key aspects of 4-Mmph's toxicological profile, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and possible endocrine disruption. The findings indicate significant acute toxicity with variability among species, a high potential for adverse effects in the gastrointestinal system and lungs, a low genotoxic potential, a significant likelihood of skin irritation, and a notable cardiotoxicity risk associated with hERG channel inhibition. Evaluation of endocrine disruption revealed a low likelihood that 4-Mmph interacts with the estrogen receptor alpha (ER-α), indicating minimal estrogenic activity. These insights, derived from in silico studies, play a crucial role in improving the comprehension of 4-Mmph in forensic and clinical toxicology. These initial toxicological inquiries establish the foundation for future investigations and help formulate risk assessment and management strategies regarding the use and abuse of NPS. This article is part of a larger project funded by the Polish Ministry of Education and Science, titled "Toxicovigilance, Poisoning Prevention, and First Aid in Poisoning with Xenobiotics of Current Clinical Importance in Poland" (Grant Number SKN/SP/570184/2023).
Assuntos
Simulação por Computador , Metilfenidato , Psicotrópicos , Metilfenidato/toxicidade , Metilfenidato/análogos & derivados , Humanos , Psicotrópicos/toxicidade , Animais , Disruptores Endócrinos/toxicidade , Cardiotoxicidade/etiologia , Receptor alfa de Estrogênio/metabolismo , Testes de Mutagenicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Dose Letal MedianaRESUMO
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1-4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute "binge" (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Fator Neurotrófico Derivado do Encéfalo , Metanfetamina , Ratos Sprague-Dawley , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Metanfetamina/toxicidade , Metanfetamina/administração & dosagem , Metanfetamina/farmacologia , Masculino , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Estimulantes do Sistema Nervoso Central/farmacologia , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/efeitos dos fármacos , Modelos Animais de Doenças , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
The abuse of methamphetamine is a significant threat to cardiovascular health and has detrimental effects on the myocardium. The present study aims to explore potential interventions that can mitigate myocardial pyroptosis in rats following methamphetamine withdrawal. A total of 104 male Wistar rats were randomly assigned to eight groups. The rats underwent a methamphetamine administration protocol, receiving intraperitoneal injections of 10 mg/kg during the 1st week, followed by a weekly dose escalation of 1 mg/kg from the second to the 6th week and two times per day. Concurrently, the rats engaged in 6 weeks of moderate-intensity treadmill aerobic training, lasting 60 min per day, 5 days a week. Simultaneously, the Nutrition bio-shield Superfood (NBS) supplement was administered at a dosage of 25 g/kg daily for 6 weeks. The study assessed the expression levels of Caspase-1, Interleukin-1beta (IL-1ß), and Interleukin-18 (IL-18) genes in myocardial tissue. Data analysis utilized a one-way analysis of variance (p ≤ 0.05). The findings revealed that methamphetamine usage significantly elevated the expression of Caspase-1, IL-1ß, and IL-18 genes (p ≤ 0.05). Conversely, methamphetamine withdrawal led to a notable reduction in the expression of these genes (p ≤ 0.05). Noteworthy reductions in Caspase-1, IL-1ß, and IL-18 expression were observed following aerobic training, supplementation, and the combined approach (p ≤ 0.05). The chronic use of methamphetamine was associated with cardiac tissue damage. This study highlights the potential of aerobic training and NBS Superfood supplementation in mitigating the harmful effects of methamphetamine-induced myocardial pyroptosis. The observed reductions in gene expression levels indicate promising interventions to address the cardiovascular consequences of methamphetamine abuse. The findings of this study suggest that a combination of aerobic exercise and NBS Superfood supplementation can provide a promising approach to mitigate the deleterious effects of methamphetamine on the heart. These findings can be useful for healthcare professionals and policymakers to design effective interventions to prevent and manage the adverse effects of methamphetamine abuse.
Assuntos
Cardiotoxicidade , Suplementos Nutricionais , Modelos Animais de Doenças , Cardiopatias , Interleucina-18 , Metanfetamina , Condicionamento Físico Animal , Piroptose , Ratos Wistar , Animais , Metanfetamina/toxicidade , Metanfetamina/administração & dosagem , Masculino , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Piroptose/efeitos dos fármacos , Interleucina-18/metabolismo , Interleucina-18/genética , Cardiopatias/induzido quimicamente , Cardiopatias/prevenção & controle , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Cardiopatias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/prevenção & controle , Caspase 1/metabolismo , Caspase 1/genética , Estimulantes do Sistema Nervoso Central/toxicidade , Estimulantes do Sistema Nervoso Central/administração & dosagem , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Fatores de TempoRESUMO
BACKGROUND: Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)-derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs-derived exosomes on cognitive function and neurogenesis of METH-addicted rodents. METHODS: Male BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs-derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis-related factors, including NeuN and DCX, and the expression of Iba-1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF-α and NF-κB, were evaluated by western blotting. RESULTS: The results showed that BMSCs-exosomes improved the time spent in the target quadrant and correct-to-wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF-α and NF-κB. Besides, BMSC-exosomes down-regulated the expression of Iba-1. CONCLUSION: Our findings indicate that BMSC-exosomes mitigated METH-caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Proteína Duplacortina , Exossomos , Hipocampo , Células-Tronco Mesenquimais , Metanfetamina , Camundongos Endogâmicos BALB C , Neurogênese , Animais , Exossomos/metabolismo , Masculino , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Camundongos , Metanfetamina/toxicidade , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Proteínas dos Microfilamentos/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Proteínas de Ligação ao Cálcio , Proteínas de Ligação a DNARESUMO
Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8-14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY's ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug's antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent.
Assuntos
Antioxidantes , Doxiciclina , Hipocampo , Mania , Neurônios , Animais , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Antioxidantes/farmacologia , Mania/induzido quimicamente , Mania/tratamento farmacológico , Doxiciclina/farmacologia , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Anfetamina/farmacologia , Anfetamina/toxicidade , Modelos Animais de Doenças , Estimulantes do Sistema Nervoso Central/toxicidade , Monoaminas Biogênicas/metabolismo , Dextroanfetamina/farmacologia , Dextroanfetamina/toxicidade , Antimaníacos/farmacologia , Fármacos Neuroprotetores/farmacologiaRESUMO
Methamphetamine (MA), a representative amphetamine-type stimulant, is one of the most abused drugs worldwide. Studies have shown that MA-induced neurotoxicity is strongly associated with oxidative stress and apoptosis. While nuclear factor E2-related factor 2 (Nrf2), an antioxidant transcription factor, is known to exert neuroprotective effects, its role in MA-induced dopaminergic neuronal apoptosis remains incompletely understood. In the present study, we explored the effects of MA on the expression levels of Nrf2, dynamin-related protein 1 (Drp1), mitofusin 1 (Mfn1), cytochrome c oxidase (Cyt-c), and cysteine aspartate-specific protease 3 (Caspase 3), as well as the correlations between Nrf2 and mitochondrial dynamics and apoptosis. Brain tissue from MA abusers was collected during autopsy procedures. An MA-dependent rat model was also established by intraperitoneal administration of MA (10 mg/kg daily) for 28 consecutive days, followed by conditioned place preference (CPP) testing. Based on immunohistochemical staining and western blot analysis, the protein expression levels of Nrf2 and Mfn1 showed a decreasing trend, while levels of Drp1, Cyt-c, and Caspase 3 showed an increasing trend in the cerebral prefrontal cortex of both MA abusers and MA-dependent rats. Notably, the expression of Nrf2 was positively associated with the expression of Mfn1, but negatively associated with the expression levels of Drp1, Cyt-c, and Caspase 3. These findings suggest that oxidative stress and mitochondrial fission contribute to neuronal apoptosis, with Nrf2 potentially playing a critical role in MA-induced neurotoxicity.
Assuntos
Apoptose , Metanfetamina , Dinâmica Mitocondrial , Fator 2 Relacionado a NF-E2 , Córtex Pré-Frontal , Animais , Metanfetamina/farmacologia , Metanfetamina/toxicidade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Dinâmica Mitocondrial/fisiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Ratos , Humanos , Adulto , Ratos Sprague-Dawley , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Dinaminas/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/toxicidade , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Pessoa de Meia-Idade , Adulto Jovem , FemininoRESUMO
Methamphetamine (METH) is a widely abused amphetamine-type psychoactive drug that causes serious health problems. Previous studies have demonstrated that METH can induce neuron autophagy and apoptosis in vivo and in vitro. However, the molecular mechanisms underlying METH-induced neuron autophagy and apoptosis remain poorly understood. Stromal interacting molecule 1 (STIM1) was hypothesized to be involved in METH-induced neuron autophagy and apoptosis. Therefore, the expression of STIM1 protein was measured and the effect of blocking STIM1 expression with siRNA was investigated in cultured neuronal cells, and the hippocampus and striatum of mice exposed to METH. Furthermore, intracellular calcium concentration and endoplasmic reticulum (ER) stress-related proteins were determined in vitro and in vivo in cells treated with METH. The results suggested that STIM1 mediates METH-induced neuron autophagy by activating the p-Akt/p-mTOR pathway. METH exposure also resulted in increased expression of Orai1, which was reversed after STIM1 silencing. Moreover, the disruption of intracellular calcium homeostasis induced ER stress and up-regulated the expression of pro-apoptotic protein CCAAT/enhancer-binding protein homologous protein (CHOP), resulting in classic mitochondria apoptosis. METH exposure can cause neuronal autophagy and apoptosis by increasing the expression of STIM1 protein; thus, STIM1 may be a potential gene target for therapeutics in METH-caused neurotoxicity.
Assuntos
Apoptose , Autofagia , Estresse do Retículo Endoplasmático , Metanfetamina , Neurônios , Molécula 1 de Interação Estromal , Metanfetamina/toxicidade , Animais , Molécula 1 de Interação Estromal/metabolismo , Molécula 1 de Interação Estromal/genética , Autofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Estimulantes do Sistema Nervoso Central/toxicidade , Cálcio/metabolismo , Células Cultivadas , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Proteína ORAI1/metabolismo , Proteína ORAI1/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genética , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologiaRESUMO
Methamphetamine (METH) is a highly addictive psychostimulant known for its profound impact on the nervous system. Chronic METH use leads to neurotoxicity characterized by various molecular and structural alterations in the brain. This review article primarily aims to elucidate the mechanisms underlying METHinduced neurotoxicity. METH's mechanism of action involves the inhibition of dopamine, serotonin, and norepinephrine reuptake, resulting in altered synaptic function. Prolonged METH exposure triggers oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, impaired axonal transport, autophagy, and programmed cell death, ultimately contributing to neurotoxicity. These neurotoxic effects manifest as increased neuronal firing rate, disruptions in intracellular ion balance (Ca2+ and Na+), energy production imbalances, and excessive reactive oxygen species production. The bloodbrain barrier is compromised, leading to structural, functional, and neurochemical alterations, particularly in the frontostriatal circuit. While our comprehensive review addresses these intricate molecular and structural changes induced by METH, we also examined the latest therapeutic strategies designed to mitigate neurotoxicity. Our investigation sheds light on the critical need to comprehend the complex pathways underlying METHinduced neurotoxicity and develop effective treatment approaches.