Methamphetamine-induced Neurotoxicity Research Articles

IGFBP5 Promotes Neuronal Apoptosis in a 6-OHDA-Toxicant Model of Parkinson’s Disease by Inhibiting the Sonic Hedgehog Signaling Pathway

Introduction: Parkinson’s disease (PD) is the most common neurodegenerative disease worldwide. Studies have shown that insulin-like growth factor-binding protein 5 (IGFBP5) may contribute to methamphetamine-induced neurotoxicity and neuronal apoptosis in PC-12 cells and rat striatum. Here, we studied the expression and role of IGFBP5 in the 6-OHDA-toxicant model of PD. Methods: PC-12 and SH-SY5Y cells were exposed to 50 μm 6-OHDA for 24 h. qRT-PCR, western blotting, CCK-8 assay, EdU staining, annexin V staining, and immunofluorescence were performed to study the effects of IGFBP5-specific siRNAs. The effects of IGFBP5 on a rat 6-OHDA model of PD were confirmed by performing behavioral tests, tyrosine hydroxylase (TH) immunofluorescence staining, and western blotting. Results: In the GSE7621 dataset, IGFBP5 was highly expressed in the substantia nigra tissues of PD patients compared to healthy controls. In PC-12 and SH-SY5Y cells, IGFBP5 was upregulated following 6-OHDA exposure in a dose-dependent manner. Silencing of IGFBP5 promoted PC-12 and SH-SY5Y proliferation and inhibited apoptosis under 6-OHDA stimulation. Silencing of IGFBP5 relieved 6-OHDA-induced TH-positive neuron loss. Hedgehog signaling pathway was predicted as a downstream signaling pathway of IGFBP5. Negative regulation between IGFBP5 and sonic hedgehog (SHH) signaling pathway was confirmed in vitro. The effects of IGFBP5 silencing on SH-SY5Y cells were partially reversed using cyclopamine, a direct inhibitor of the SHH signaling pathway. In addition, silencing of IGFBP5 attenuated motor deficits and neuronal damage in 6-OHDA-induced PD rats. Conclusion: Elevated IGFBP5 expression may be involved in 6-OHDA-induced neurotoxicity through regulation of the SHH signaling pathway.

The Synergistic Effect of Curcumin and Piperine Nanoparticles on Methamphetamine-induced Neurotoxicity, Oxidative Stress, and Memory Impairments in Mice Brain

Background: Methamphetamine (METH) is a highly addictive neural stimulant that severely affects the CNS and can induce oxidative damage. Piperine and curcumin are active constituents that have numerous properties, including antioxidant, anti-inflammatory, and neuroprotective Objective: In this study, the synergistic effect of piperine and curcumin nanoparticles was investigated on the acute doses of METH-induced neurotoxicity in mice brains. Methods: METH (6 mg/kg, i.p) was administered to 14 groups of mice and piperine-curcumin nanoparticles at different doses (10, 20, 40 mg/kg and 20, 40 and 60 mg/kg, respectively) were administered. Open field test (OFT) and conditioned place preference (CPP) were used to investigate locomotor activity, anxiety-like behavior, and addictive behavior in mice. Oxidative stress biomarkers (reactive oxygen species (ROS), protein carbonyl content, lipid peroxidation, glutathione content, and mitochondrial function were evaluated in isolated brain mitochondria. Results: We found that piperine and curcumin nanoparticles significantly decreased hyperlocomotion and anxiety-like behavior in METH-treated mice. Also, METH enhanced CPP whilst piperine and curcumin nanoparticles suppressed the effect of METH-induced CPP. METH administration significantly increased ROS, protein carbonyl content, and lipid peroxidation and decreased glutathione content and mitochondrial function in the isolated brain mitochondria. Piperine and curcumin nanoparticles (at all doses) showed synergistic effects on reducing oxidative damages in a dosedependent manner compared to the METH group. Conclusion: In conclusion, combined piperine and curcumin nanoparticles showed greater neuroprotective effects against METH-induced neurotoxicity due to their greater permeability and better antioxidant properties than piperine and curcumin alone

Protective effects of alpha-lipoic acid on anxiety-like behavior, memory and prevention of hippocampal oxidative stress in methamphetamine-treated rats.

Alpha-lipoic acid is an essential cofactor for aerobic metabolism and acts as a potent antioxidant in the body. It has been shown that acute exposure to methamphetamine induces oxidative stress, which is responsible for severe cognitive deficits in animals. The hippocampus plays a crucial role in the processing of memory and anxiety-like behavior. In this study, preventive effect of the alpha-lipoic acid on memory impairment in methamphetamine-induced neurotoxicity was investigated. Wistar male rats (200-220g) were allocated to five groups (seven rats in each group): (1) saline + saline, (2) saline + vehicle (sunflower oil as alpha-lipoic acid solvent), (3) methamphetamine + vehicle, (4) methamphetamine + alpha-lipoic acid 10mg/kg, and (5) methamphetamine + alpha-lipoic acid 40mg/kg. Rats received intraperitoneal methamphetamine repeatedly (2 × 20mg/kg, 2h interval). Alpha-lipoic acid was injected 30min, 24h, and 48h after the last injection of methamphetamine. The passive avoidance test and open field were used for evaluation of memory retrieval and anxiety, respectively. After behavioral test, rats were anesthetized, their brains were extracted, and after preparing hippocampal homogenates, malondialdehyde (MDA) level, catalase, and superoxide dismutase (SOD) activities were evaluated. Statistical analysis showed that injection of saline or sunflower oil had no significant effect on anxiety, memory, or oxidative stress markers. Methamphetamine induced memory impairment, increased anxiety-like behavior and MDA level, but it reduced catalase and SOD activity. Treatment with alpha-lipoic acid decreased MDA, increased catalase and SOD activity, and also prevented memory impairment and anxiety-like behavior. Our results showed that alpha-lipoic acid protected the hippocampus from oxidative stress by elevating SOD and CAT activities and reduced memory impairment following acute methamphetamine injection. These findings suggest that alpha-lipoic acid may have a protective effect against the adverse effects of methamphetamine exposure on the hippocampus. Therefore, the current data indicated that ALA can reduce oxidative stress predominantly by its antioxidant property.

The Role of Non-coding RNAs in Methamphetamine-Induced Neurotoxicity.

Methamphetamine (METH) is an amphetamine-type stimulant that is highly toxic to the central nervous system (CNS). Repeated intake of METH can lead to addiction, which has become a globalized problem, resulting in multiple public health and safety problems. Recently, the non-coding RNA (ncRNA) has been certified to play an essential role in METH addiction through various mechanisms. Herein, we mainly focused on three kinds of ncRNAs including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which are involved in neurotoxicity effects such as cognitive impairment, behavioral abnormalities, and psychiatric disorders due to METH abuse. In addition, differential expression (DE) ncRNAs also suggest that specific responses and sensitivity to METH neurotoxicity exist in different brain regions and cells. We summarized the relationships between the ncRNAs and METH-induced neurotoxicity and psychiatric disturbances, respectively, hoping to provide new perspectives and strategies for the prevention and treatment of METH abuse. Schematic diagram of the non-coding RNAs (ncRNAs) was involved in methamphetamine (METH)-induced neurotoxicity. The ncRNAs were involved in METH-induced blood-brain barrier disruption, neuronal, astrocyte, and microglial damage, and synaptic neurotransmission impairment. The study of ncRNAs is a hot spot in the future to further understand the neurotoxicity of METH and provide more favorable scientific support for clinical diagnosis and innovation of related treatments.

Ethanol Extract of Centella asiatica Improved Methamphetamine-Induced Neurotoxicity on Mouse Model via Stimulating Superoxide Dismutase II and microRNA-34A Expression

Neurotoxicity induced by a psychostimulant drug, methamphetamine (METH) is associated with devastating and persistent neurotoxicity effects on the central nervous system (CNS). Centella asiatica (CA) is known as an antioxidant and neuroprotective agent. However, there is a limited study on natural-derived therapeutic to attenuate neurotoxicity induced by METH. We aimed to investigate the effects of METH and ethanol extract CA (CAE) on motor performance of animal model and the expression of manganese superoxide dismutase II (SOD2) and microRNA-34a (miR-34a) in the brain tissue. Male Sprague-Dawley rats were administered with METH (50 mg/kg per body weight) twice per day for 4 days, CAE (300 mg/kg & 500 mg/kg per body weight for 21 days and combination of METH and CAE for 21 day(s). Weight of rat was measured and motor performance was evaluated using vertical pole and narrow beam tests. Expression of SOD2 and miR-34a were measured using Quantitative Real-time Polymerase Chain Reaction (RT-qPCR). Group III (300 mg/kg CAE); p<0.001, Group IV (500 mg/kg CAE); p<0.001, Group V (METH+300 mg/kg CAE); p<0.01 and Group VI (METH+500 mg/kg CAE); p<0.01 significantly improved latency in the vertical pole test compared to METH group. Meanwhile, Group III (300 mg/kg CAE); p<0.001 and Group IV (500 mg/kg CAE); p<0.001 significantly decreased latency in the narrow beam test compared to METH. Post-treatment of CAE on METH-treated rats, Group V (METH+300 mg/kg CAE) and Group VI (METH+500 mg/kg CAE) non-significantly upregulated the SOD2 expression by 3.78±1.03 and 4.05±0.19 folds compared to METH, respectively. Post-treatment of CAE on METH-treated rats, Group V (METH+300 mg/kg CAE) and Group VI (METH+500 mg/kg CAE) non-significantly upregulated the miR-34a expression by (7.02±3.73) and (6.75±1.94) folds compared to METH, respectively. CAE could be suggested as a promising natural-derived therapeutic for METH-induced neurotoxicity to ameliorating motor performance and triggering SOD2 and miR-34a expression.

Neuroprotective effect of thyroid hormones on methamphetamine-induced neurotoxicity via cell surface receptors

Thyroid hormones (THs) have an essential role in normal brain development and function. Methamphetamine (MA) is a widely abused psychostimulant that induces irreversible damages to neuronal cells. In the current study, we used rat primary hippocampal neurons (PHNs) to investigate the neuroprotective effect of THs against MA neurotoxicity. PHNs were prepared from 18-day rat embryos and cell viability was assessed using MTT assay, following treatment with various concentrations of MA, T3, T4 or tetrac, an integrin αvβ3 cell surface receptor antagonist. Our results showed that 7 mM MA induced an approximately 50 % reduction in the PHNs viability. Treatment with 800 nM T3 or 8 μM T4 protected PHNs against MA toxicity, an effect which was blocked in the presence of tetrac. These findings suggest that THs protect PHNs against MA-induced cell death by the activation of integrin αvβ3 cell surface receptors. So, targeting integrin αvβ3 receptors or using THs can be considered as promising therapeutic strategies to overcome MA neurotoxicity.

Methamphetamine Use: A Narrative Review of Adverse Effects and Related Toxicities

Methamphetamine has been labeled "America's most dangerous drug" and has received significant public health attention. Stimulant addiction and tolerance are heavily documented in the literature; increasingly larger doses maintain euphoria in short time periods to withstand stimulant tolerance. Stimulant deaths are high in the United States and abroad. Between 2013 and 2019, deaths related to methamphetamine use quadrupled from 3,616 to 16,127. Methamphetamine use increased four-fold from 2015 to 2016. Due to this increase in methamphetamine use and its associated medical complications, the mortality rate associated with methamphetamine use has doubled over the past ten years. Cardiopulmonary symptoms include chest pain, palpitations, and shortness of breath. Methamphetamine-related myocardial infarction can also occur. Central nervous system symptoms include agitation, anxiety, delusions, hallucinations, and seizures. Methamphetamine-induced psychosis may unmask underlying psychiatric disorders. It can also cause cerebral vasculitis, which elicits cortical blindness and ischemic strokes. Methamphetamine-induced neurotoxicity in serotonergic systems is more diffuse, involving the striatum, hippocampus, septum, amygdala, and hypothalamus leading to mood changes, psychosis, and memory impairment. This narrative review will aim to highlight the adverse effects as well as the toxicity that can occur with methamphetamine use.

Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2.

In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH use disorders. Cannabidiol (CBD), a major non-psychoactive (and non-addictive) cannabinoid from the cannabis plant, shows neuroprotective, antioxidative, and anti-inflammatory properties under METH exposure. At present, however, the mechanisms underlying these properties remain unclear, which continues to hinder research on its therapeutic potential. In the current study, computational simulations showed that CBD and METH may directly bind to the dopamine receptor D1 (DRD1) via two overlapping binding sites. Moreover, CBD may compete with METH for the PHE-313 binding site. We also found that METH robustly induced apoptosis with activation of the caspase-8/caspase-3 cascade in-vitro and in-vivo, while CBD pretreatment prevented these changes. Furthermore, METH increased the expression of DRD1, phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) at serine 421 (Ser421), and level of intracellular Ca2+ in-vitro and in-vivo, but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca2+ overload in-vitro. In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca2+ overload, which were blocked by CBD pretreatment in-vitro. These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca2+ signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding.

Protection of the PC12 Cells by Nesfatin-1 Against Methamphetamine-Induced Neurotoxicity

Protection of the PC12 Cells by Nesfatin-1 Against Methamphetamine-Induced Neurotoxicity

MicroRNAs in Methamphetamine-Induced Neurotoxicity and Addiction.

Methamphetamine (METH) abuse remains a significant public health concern globally owing to its strong addictive properties. Prolonged abuse of the drug causes irreversible damage to the central nervous system. To date, no efficient pharmacological interventions are available, primarily due to the unclear mechanisms underlying METH action in the brain. Recently, microRNAs (miRNAs) have been identified to play critical roles in various cellular processes. The expression levels of some miRNAs are altered after METH administration, which may influence the transcription of target genes to regulate METH toxicity or addiction. This review summarizes the miRNAs in the context of METH use, discussing their role in the reward effect and neurotoxic sequelae. Better understanding of the molecular mechanisms involved in METH would be helpful for the development of new therapeutic strategies in reducing the harm of the drug.

Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation

RationaleMethamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions.ObjectivesTherefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice.MethodsMice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology.ResultsUnder these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices.ConclusionsTogether, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

The The Effects of Centella asiatica Extract (CAE) on Methamphetamine-Induced Neurotoxicity via Human Neuroblastoma Cell Line

Methamphetamine (METH) was reported to caused neurotoxicity and cell death, in vitro. Centella asiatica or ‘pegaga’ is a native tropical herb with antioxidant and neuroprotective activities. Although the effects of Centella asiatica against oxidative stress and neuronal cell death have been reported in previous studies, however, the potential effects of Centella asiatica against psychostimulant methamphetamine (METH) are limited. Therefore, this study was aimed to evaluate the effects of Centella asiatica extract (CAE) against METH on all-trans retinoic acid, RA-differentiated human neuroblastoma, SH-SY5Y cells. The RA-differentiated SH-SY5Y cells were used to resemble dopaminergic neuronal-like cells. Cell viability was quantitatively assessed by 3-(4,5-dimethylthiazol-2-yl)-2 tetrazolium bromide, MTS assay. CAE at varying concentrations from 1pg/mL to 1mg/mL significantly decreased the viability of the undifferentiated SH-SY5Y cells in a concentration-dependent manner. At 1mg/mL of CAE, significantly increased the viability of differentiated SH-SY5Y cells. Meanwhile, CAE at 100µg/mL and 1mg/mL significantly reversed the METH-induced neuronal cell death. The results revealed that promising treatment of CAE on METH-induced neurotoxicity is mediated by its high content of asiaticoside, asiatic acid, madecassoside and madecassic acid. Taken together, this study may suggest CAE as a potential therapeutic treatment for METH-induced neurotoxicity, in vitro.

Fucoxanthin alleviates methamphetamine-induced neurotoxicity possibly via the inhibition of interaction between Keap1 and Nrf2

Fucoxanthin, a carotenoid from edible algae such as Sargassum horneri, has been widely used as a functional food for treating obesity, and was reported to produce neuroprotective effects against various neurotoxins. Here we evaluated the anti-methamphetamine neuroprotective effects of fucoxanthin in PC12 cells. Pretreatment with fucoxanthin prevented methamphetamine-induced increase of reactive oxygen species (ROS) and neuronal apoptosis. Furthermore, fucoxanthin increased the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme positively regulated by Nrf2. In addition, fucoxanthin could reverse the decreased expression of phospho-Ser473-Akt, an upstream molecule which prevents Nrf2 degradation and increases Nrf2 nuclear translocation. Most importantly, fucoxanthin showed a high affinity with Kelch-like ECH-associated protein-1 (Keap1), via the action on Keap1-Nrf2 binding pocket, suggesting that fucoxanthin might also facilitate the dissociation of Keap1-Nrf2 complex, and enhance Nrf2 nuclear translocation. All these results implied that fucoxanthin might be developed as an antidote of methamphetamine.

Possible repair mechanisms of renin-angiotensin system inhibitors, matrix metalloproteinase-9 inhibitors and protein hormones on methamphetamine-induced neurotoxicity.

Methamphetamine is a highly addictivecentral stimulant with extensive and strong neurotoxicity. The neurotoxicity of methamphetamine is closely related to the imbalance of dopamine levels and the destruction of the blood-brain barrier. An increase in dopamine may induce adverse effects such as behavioral sensitization and excessive locomotion. Damage to the blood-brain barrier can cause toxic or harmful substances to leak to the central nervous system, leading to neurotoxicity. The renin-angiotensin system is essential for the regulation of dopamine levels in the brain. Matrix metalloproteinase-9 causes reward effects and behavioral sensitization by inducing dopamine release. Prolactin has been shown to be involved in the regulation of tight junction proteins and the integrity of the blood-brain barrier. At present, the treatment of methamphetamine detoxification is still based on psychotherapy, and there is no specific medicine. With the rapid increase in global seizures of methamphetamine, the treatment of its toxicity has attracted more and more attention. This review intends to summarize the therapeutic mechanisms of renin-angiotensin inhibitors, matrix metalloproteinase-9 inhibitors and protein hormones (prolactin) on methamphetamine neurotoxicity. The repair effects of these three on methamphetamine may be related to the maintenance of brain dopamine balance and the integrity of the blood-brain barrier. This review is expected to provide the new therapeutic strategy of methamphetamine toxicity.

Electroconvulsive seizures protect against methamphetamine-induced inhibition of neurogenesis in the rat hippocampus

Following methamphetamine consumption and during abstinence many behavioral consequences emerge (i.e., cognitive deficits, ongoing episodes of psychosis, depression, severe cravings, brain neurotoxicity), which are likely linked to propensity to relapse. In this line of thought, we recently showed that binge methamphetamine administration enhanced negative affect and voluntary drug consumption in rats, while it induced persistent neurotoxic effects (i.e., impaired hippocampal neurogenesis), effects that emerged long after drug removal. To date, no pharmacological strategies have been proven to be effective for the treatment of methamphetamine toxicity. A few studies have evaluated the impact of combining methamphetamine pretreatment with electroconvulsive seizures (ECS) post-treatment, an alternative non-pharmacological option used in psychiatry for resistant depression that offers a safe and really potent therapeutic response. Against this background, the present study aimed at testing whether repeated ECS treatment could ameliorate some of the long-term neurotoxicity effects induced by adolescent methamphetamine exposure in rats and emerging after drug removal. At the behavioral level, the main results showed that methamphetamine administration did not alter negative affect immediate during adolescence or later on in adulthood. Interestingly, repeated ECS improved the negative impact of methamphetamine administration on reducing hippocampal neurogenesis, demonstrating that ECS can attenuate certain degree of methamphetamine-induced neurotoxicity in rats, and suggesting ECS as a good therapeutical candidate that deserves further studies.

Effects of a novel tamoxifen‐analogue (6c) on methamphetamine induced neurotoxicity

The use and abuse of psychostimulants have been associated with countless adverse effects (including addiction, neurotoxicity and death) and billions of dollars of damage to the global economy. Yet, to date, there is no effective pharmacotherapeutic. Amphetamine has been shown to activate the β-isoform of protein kinase C (PKC), which phosphorylates the dopamine transporter (DAT) at N-terminal serines and threonines to increase extracellular dopamine. Recently, a novel PKC inhibitor (6C) has been developed to attenuate or block amphetamine use and addiction. Prior studies have shown that the administration of 6C with amphetamine inhibited amphetamine monoamine release, hyperlocomotion and self-administration.1 Although the neurotoxicity accompanying the acute and chronic use of amphetamine and methamphetamine are well characterized, no treatment exists for the neurotoxicity associated with their use. To assess the potential of 6C to impact psychostimulant-induced neurotoxicity (and extend its therapeutic efficacy in psychostimulant abuse), female mice received a single injection of 0 (vehicle) or 6 mg/kg of 6C subcutaneously 2 h prior to a binge-like regimen of 5 mg/kg of methamphetamine or saline during which mice were injected with 5 mg/kg of methamphetamine or saline (IP) every 2 h for a total of four injections. Two days following injections, mice were euthanized by decapitation for brain removal. The striatum was dissected from both sides of the brain. Each side of the striatum was frozen separately using dry ice and stored at −80°C until analysis occurred. As shown in Figure 1, 6C significantly reduced methamphetamine-induced neurotoxicity when probing for DAT and tyrosine hydroxylase (TH) (western/immunoblot analysis) and DA levels (HPLC). To assess any generalization of these effects of 6C on psychostimulant intake and neurotoxicity, similar analyses will be made with a new class of beta ketone analogues of amphetamine, the synthetic cathinones, whose reinforcing effects are mediated by neurochemical mechanisms similar to and different from those of amphetamine2. 1. C. Carpenter, A. G. Zestos, R. Altshuler, R. J. Sorenson, B. Guptaroy, H. D. Showalter, R. T. Kennedy, E. Jutkiewicz and M. E. Gnegy, Neuropsychopharmacology, 2017, 42, 1940-1949. 2. A. L. Riley, K. Nelson, P. To, R. López-Arnau, P. Xu, D. Wang, Y. Wang, H-W. Shen, D. Kuhn, M. Angoa-Perez, J. Anneken, D. Muskiewicz, and F. Hall. Neuroscience & Biobehavioral Reviews, 2020, 110, 150-173.

6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways.

Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4′-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases.

Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors.

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.

Curcumin attenuates spatial memory impairment by anti-oxidative, anti-apoptosis, and anti-inflammatory mechanism against methamphetamine neurotoxicity in male Wistar rats: Histological and biochemical changes

ObjectiveMethamphetamine is used extensively around the world as a psychostimulant. The complications related to methamphetamine include methamphetamine-induced neurotoxicity, mainly involving intraneuronal processes, such as oxidative stress and excitotoxicity. Curcumin is effective against neuronal injury due to its antioxidant, anti-inflammatory effects. In this study, we examined the protective effects of curcumin against methamphetamine neurotoxicity. MethodsSixty male Wistar rats were divided into the following groups: control (n = 12), DMSO (n = 12), methamphetamine (n = 12), and methamphetamine + curcumin (100 and 200 mg/kg, respectively, intraperitoneal [IP]; n = 12). Neurotoxicity was induced by 40 mg/kg of methamphetamine administrated through 4 injections (4 × 10 mg/kg, q2h, IP). Curcumin (100 and 200 mg/kg) was administered at 7 days after the last methamphetamine injection. By using a Morris water maze task, the hippocampus-dependent memory and spatial learning were evaluated 1 day after the last curcumin injection. Then, the animal brains were isolated for biochemical measurements, as well as glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba-1) and caspase-3 immunohistochemical staining. ResultsThe current study demonstrated that administration of curcumin significantly attenuates spatial memory impairment (P < 0.01) following methamphetamine neurotoxicity. Curcumin caused a significant increase in the levels of superoxide dismutase and glutathione peroxidase (P < 0.05). However, it decreased tumor necrosis factor (TNF-α) (P < 0.05) and malondialdehyde (P < 0.01) levels as compared to the methamphetamine group. Also, curcumin significantly reduced Iba-1 (P < 0. 01), GFAP and caspase-3 positive cells in the hippocampus (P < 0.001). ConclusionCurcumin exerted neuroprotective effects on methamphetamine neurotoxicity because of its antioxidant and anti-inflammatory effect.

Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway.

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.