Methamphetamine Neurotoxicity Research Articles

Astrocyte‐selective STAT3 knockdown rescues methamphetamine withdrawal‐disrupted spatial memory in mice via restoring the astrocytic capacity of glutamate clearance in dCA1

Methamphetamine (METH) is a common abused drug. METH-triggered glutamate (Glu) levels in dorsal CA1 (dCA1) could partially explain the etiology of METH-caused abnormal memory, but the synaptic mechanism remains unclear. Here, we found that METH withdrawal disrupted spatial memory in mice, accompanied by the increases in Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, as indicated by increasing the A1-like astrocytes and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), decreasing the Glu transporter 1(GLT-1, also known as EAAT2 or SLC1A2), Glu-aspartate-transporter (GLAST also known as EAAT1 or SLC1A3) and astrocytic glutamine synthase (GS), but failed to affect the presynaptic Glu release from dCA3 within dCA1. Moreover, we identified that in vitro A1-like astrocytes exhibited an increased STAT3 activation and the impaired capacity of Glu clearance. Most importantly, selective knockdown of astrocytic STAT3 in vivo in dCA1 restored the astrocytic capacity of Glu clearance, normalized Glu levels at dCA1 synapses, and finally rescued METH withdrawal-disrupted spatial memory in mice. Thus, astrocytic Glu clearance system, especially STAT3, serves as a novel target for future therapies against METH neurotoxicity.

Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity.

Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.

Non-coding RNA: insights into the mechanism of methamphetamine neurotoxicity

Chronic exposure of the methamphetamine has been shown to lead to neurotoxicity in rodents and humans. The manifestations of methamphetamine neurotoxicity include methamphetamine use disorder, methamphetamine abuse, methamphetamine addiction and methamphetamine behavioral sensitization. Repeated use of methamphetamine can cause methamphetamine use disorder. The abuse and addiction of methamphetamine are growing epidemic worldwide. Repeated intermittent exposure to methamphetamine can cause behavioral sensitization. In addition, many studies have shown that changes in the expression of non-coding RNA in the ventral tegmental area and nucleus accumbens will affect the behavioral effects of methamphetamine. Non-coding RNA plays an important role in the behavioral effects of methamphetamine. Therefore, it is important to study the relationship between methamphetamine and non-coding RNA. The purpose of this review is to study the non-coding RNA associated with methamphetamine neurotoxicity to search for the possible therapeutic target of the methamphetamine neurotoxicity.

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.

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions.

Resveratrol attenuates methamphetamine-induced memory impairment via inhibition of oxidative stress and apoptosis in mice.

Methamphetamine (METH) abuse produces serious neurotoxicity to the central nervous system along with long-term cognitive dysfunction. Resveratrol, a natural polyphenol, has broad application prospects in the treatment of neurodegenerative diseases. Therefore, this study was conducted to investigate whether resveratrol might alleviate METH-induced memory deficits in vivo. We found that multiple exposures to METH significantly impaired cognitive functions and caused long-lasting memory deficits (p<.05). Pretreatment of resveratrol (10 or 100mg/kg) remarkably attenuated METH-induced memory impairment in mice (p<.05). Bioinformatics analysis results showed that resveratrol might alleviate memory deficits by inhibiting METH-induced oxidative damage and apoptosis. Molecular docking showed that resveratrol had hydrogen bonding interactions with Kelch-like ECH associated protein 1 (Keap1), a repressor protein of the classic antioxidant Keap1-Nrf2 pathway. Further results validated oxidative stress parameters, apoptosis, and expression of Keap1 were significantly increased, while the translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and expression of its downstream proteins were greatly decreased in the hippocampus after METH exposure (p<.05). These changes caused by METH could be prevented by resveratrol (p<.05). Therefore, these findings suggested that the prevention of resveratrol on memory dysfunction induced by METH was possibly related to the activation of the Keap1-Nrf2 pathway and reduction of apoptosis. Supplementation of resveratrol could be a potential treatment for preventing the neurotoxicity of METH in the future. PRACTICAL APPLICATIONS: As one of the worst commonly abused psychostimulants, methamphetamine (METH) addiction produces serious complications including cognitive impairment and memory deficits. Resveratrol is a natural polyphenol that has important nutritional supplements and protective effects in the treatment of many neurodegenerative diseases. In this study, the results of bioinformatics prediction and experimental validation showed that resveratrol might effectively prevent memory impairment via the interaction with Keap1, activation of the Keap1-Nrf2 pathway, and inhibition of DNA damage and apoptotic responses post METH exposure. Therefore, these findings provide new ideas and insights into the application of resveratrol in the treatment of nervous system damage caused by METH.

URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels.

Methamphetamine is an addictive stimulant that possesses toxicity in the brain when taken repeatedly or at higher doses. Methamphetamine neurotoxicity is associated with numerous forms of mental impairment, including depression and anxiety. Evidence has also demonstrated that the endocannabinoid system is involved in the regulation of anxiety and depression. This study was designed to determine the involvement of the endocannabinoid system in anxiety- and depression-related behaviors in methamphetamine-withdrawal male NMRI mice. The elevated plus maze and forced swim test were used to assess the level of anxiety and depression. We found that methamphetamine (30 mg/kg, intraperitoneal) evoked depressive- and anxiogenic-like effects at 3 days post-administration. Injection of URB597 (5-10 ng/mouse, intracerebroventricular), 10 min before the test, prevented the emotional deficits induced by methamphetamine withdrawal. Moreover, the cannabinoid receptor type 1 antagonist AM251 (1 μg/mouse) or cannabinoid receptor type 2 antagonist AM630 (5 and 10 μg/mouse) suppressed the antidepressant activity in the methamphetamine-withdrawal mice treated with URB597. The transient receptor potential vanilloid 1 antagonist capsazepine (25 μg/mouse) prevented while capsazepine (100 μg/mouse) potentiated the antidepressant efficacy in the methamphetamine-withdrawal mice treated with URB597. The higher dose of AM630 and two higher doses of capsazepine had antidepressant efficacy, by themselves. Furthermore, capsazepine (50 μg/mouse) increased locomotion in the methamphetamine-withdrawal mice treated with URB597. The results suggest that URB597 has a potential for preventing methamphetamine withdrawal-evoked anxiety and depression. Cannabinoid type 1 receptors, cannabinoid type 2 receptors and transient receptor potential vanilloid 1 differently affect depression-related behaviors in methamphetamine-withdrawal mice treated with URB597.

Transfer of pathological α-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.

Exposure to methamphetamine exacerbates motor activities and alters circular RNA profile of cerebellum

Methamphetamine (METH) is a psychostimulant drug that acts on monoaminergic systems in the brain. There are several lines of evidence indicating the devastating effects of addictive drugs on the cerebellum. Moreover, it was shown that circular RNAs (circRNAs) have an important role in neurodegenerative disorders. Herein, we explored the effects of METH on neuronal degeneration, motor coordination and muscle activity. We also inspected METH–mediated changes in circRNA expression profiling in the cerebellum. Accordingly, exposure to METH triggered destructive effects on the coordination of movement of rats along with disturbed muscle activity. The fluorescent staining exhibited a significant increase in neurodegeneration in the cerebellum under the influence of METH. Besides, the number of calbindin positive Purkinje cells noticeably declined in METH-treated group compared with the control. In this regard, we identified and characterized differentially expressed (DE) circRNAs in the cerebellum under METH treatment, mainly located in dendritic spines. Moreover, based on feature and function analyzes of host genes of DE circRNAs, a large number of these genes were essentially involved in cell growth, death, inflammation and oxidative metabolism. Taken together, this data might imply the potential involvement of circRNAs in METH neurotoxicity as well as motor activity deficits.

Differential Responses of LINE-1 in the Dentate Gyrus, Striatum and Prefrontal Cortex to Chronic Neurotoxic Methamphetamine: A Study in Rat Brain.

Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause a broad range of severe cognitive deficits as well as neurobehavioral abnormalities when abused chronically, particularly at high doses. Cognitive deficits are related to METH neurotoxicity in the striatum and hippocampus. The activation of transposable Long INterspersed Nuclear Element 1 (LINE-1) is associated with several neurological diseases and drug abuse, but there are very limited data regarding the effects of high-dose METH on the activity of LINE-1 in the adult brain. Using real-time quantitative PCR, the present study demonstrates that the chronic administration of neurotoxic METH doses results in the increased expression of LINE-1-encoded Open Reading Frame 1 (ORF-1) in rat striatum shortly after the last dose of the drug and decreased ORF-1 expression during METH withdrawal, with dentate gyrus potentially developing “tolerance” to these METH effects. LINE-1 activation may be a new factor mediating the neurotoxic effects of chronic METH in the striatum and, therefore, a new drug target against METH-induced psychomotor impairments in chronic METH users.

High ambient temperature increases the toxicity and lethality of 3,4-methylenedioxymethamphetamine and methcathinone

RationaleMethylenedioxymethamphetamine (MDMA) and methcathinone (MCAT) are abused psychostimulant drugs that produce adverse effects in human users that include hepatotoxicity and death. Recent work has suggested a connection between hepatotoxicity, elevations in plasma ammonia, and brain glutamate function for methamphetamine (METH)-induced neurotoxicity. ObjectivesThese experiments investigated the effect of ambient temperature on the toxicity and lethality produced by MDMA and MCAT in mice, and whether these effects might involve similar mechanisms to those described for METH neurotoxicity. ResultsUnder low (room temperature) ambient temperature conditions, MDMA induced hepatotoxicity, elevated plasma ammonia levels, and induced lethality. Under the same conditions, even a very high dose of MCAT produced limited toxic or lethal effects. High ambient temperature conditions potentiated the toxic and lethal effects of both MDMA and MCAT. ConclusionThese studies suggest that hepatotoxicity, plasma ammonia, and brain glutamate function are involved in MDMA-induced lethality, as has been shown for METH neurotoxicity. The toxicity and lethality of both MDMA and MCAT were potentiated by high ambient temperatures. Although an initial mouse study reported that several cathinones were much less toxic than METH or MDMA, the present results suggest that it will be essential to assess the potential dangers posed by these drugs under high ambient temperatures.

Neuroprotective effect of gastrodin in methamphetamine-induced apoptosis through regulating cAMP/PKA/CREB pathway in cortical neuron.

Methamphetamine (MA) abuse induces neurotoxicity and causes neuronal cell apoptosis. Gastrodin is a traditional Chinese herbal medicine used for the treatment of nerve injuries, spinal cord injuries, and some central nervous system diseases as well. The present study investigated the neuroprotective effects of gastrodin against MA-induced neurotoxicity in neuronal cells and its potential protective mechanism. The primary cortex neuronal culture was divided into four groups (control group, MA group, MA + gastrodin group, and MA + gastrodin + small interfering RNA group). The neurotoxicity of MA was assessed by detecting apoptotic cells by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay and cell viability by cell counting kit 8 (CCK-8) method, the Tuj1-positive cells and the average axonal length were detected by immunofluorescence, and the expressions of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element-binding (CREB), and brain-derived neurotrophic factor (BDNF) proteins were detected by Western blot. The results of CCK-8 assay showed that 0.5 mM MA was an optimal concentration that induced neurotoxicity (p < 0.01). Pretreatment with 25 mg/L gastrodin exerted maximum protective effects on neuronal cells. The expression levels of cAMP, PKA, phosphorylated PKA, CREB, phosphorylated CREB, and BDNF proteins were decreased in the MA group, and pretreatment with gastrodin upregulated the expression levels of these proteins (p < 0.01). The expressions of PKA and CREB proteins showed no significant changes in the control group, MA group, and gastrodin group. Compared the MA + gastrodin + small interfering RNA group with MA + gastrodin group, the Tuj1-positive cells and the average axonal length were decreased significantly, while the number of apoptotic cells was increased (p < 0.05). Gastrodin has neuroprotective effects against MA-induced neurotoxicity, which exerts neuroprotective effects via regulation of cAMP/PKA/CREB signaling pathway and upregulates the expression of BDNF.

Naloxone Ameliorates Spatial Memory Deficits and Hyperthermia Induced by a Neurotoxic Methamphetamine Regimen in Male Rats

Background: Methamphetamine (METH) as a synthetic psychostimulant is being increasingly recognized as a worldwide problem, which may induce memory impairment. On the other hand, it is well established that naloxone, an opiate antagonist, has some beneficial effects on learning and memory. The present research aimed at evaluating naloxone effects on spatial learning and memory impairment triggered by a neurotoxic regimen of METH in male rats. Materials and Methods: The animals received the subcutaneous (sc) regimen of METH (4×6 mg/kg at 2-h intervals), intraperitoneal (ip) naloxone (4×1 mg/kg at 2-h intervals), or normal saline at four events. The Nal-METH group of rats received four naloxone injections (1 mg/kg, ip) 30 min before each METH injection (6 mg/kg, sc) at 2-h intervals. Seven days later, they were evaluated for spatial learning and memory in the Morris Water Maze (MWM) task. Result: METH regimen induced hyperthermia, as well as a poor performance, in the acquisition and retention phases of the task, indicating spatial learning and memory impairment compared to the controls. Naloxone administration (1 mg/kg, ip) before each METH injection led to significant attenuations of both hyperthermia and METH adverse effects on the rat performance in the MWM task. Conclusion: The results revealed that pretreatment with the opiate antagonist naloxone could prevent METH adverse effects on body temperature and memory performance. It seems that the opioidergic system and hyperthermia may, at least partially, be involved in METH effects on spatial memory. [GMJ. 2019;8:e1182]

Naloxone Ameliorates Spatial Memory Deficits and Hyperthermia Induced by a Neurotoxic Methamphetamine Regimen in Male Rats.

Background: Methamphetamine (METH) as a synthetic psychostimulant is being increasingly recognized as a worldwide problem, which may induce memory impairment. On the other hand, it is well established that naloxone, an opiate antagonist, has some beneficial effects on learning and memory. The present research aimed at evaluating naloxone effects on spatial learning and memory impairment triggered by a neurotoxic regimen of METH in male rats. Materials and Methods: The animals received the subcutaneous (sc) regimen of METH (4×6 mg/kg at 2-h intervals), intraperitoneal (ip) naloxone (4×1 mg/kg at 2-h intervals), or normal saline at four events. The Nal-METH group of rats received four naloxone injections (1 mg/ kg, ip) 30 min before each METH injection (6 mg/kg, sc) at 2-h intervals. Seven days later, they were evaluated for spatial learning and memory in the Morris Water Maze (MWM) task. Results: METH regimen induced hyperthermia, as well as a poor performance, in the acquisition and retention phases of the task, indicating spatial learning and memory impairment compared to the controls. Naloxone administration (1 mg/kg, ip) before each METH injection led to significant attenuations of both hyperthermia and METH adverse effects on the rat performance in the MWM task. Conclusion: The results revealed that pretreatment with the opiate antagonist naloxone could prevent METH adverse effects on body temperature and memory performance. It seems that the opioidergic system and hyperthermia may, at least partially, be involved in METH effects on spatial memory.

Naloxone Ameliorates Spatial Memory Deficits and Hyperthermia Induced by a Neurotoxic Methamphetamine Regimen in Male Rats

Background: Methamphetamine (METH) as a synthetic psychostimulant is being increasingly recognized as a worldwide problem, which may induce memory impairment. On the other hand, it is well established that naloxone, an opiate antagonist, has some beneficial effects on learning and memory. The present research aimed at evaluating naloxone effects on spatial learning and memory impairment triggered by a neurotoxic regimen of METH in male rats. Materials and Methods: The animals received the subcutaneous (sc) regimen of METH (4×6 mg/kg at 2-h intervals), intraperitoneal (ip) naloxone (4×1 mg/kg at 2-h intervals), or normal saline at four events. The Nal-METH group of rats received four naloxone injections (1 mg/kg, ip) 30 min before each METH injection (6 mg/kg, sc) at 2-h intervals. Seven days later, they were evaluated for spatial learning and memory in the Morris Water Maze (MWM) task. Result: METH regimen induced hyperthermia, as well as a poor performance, in the acquisition and retention phases of the task, indicating spatial learning and memory impairment compared to the controls. Naloxone administration (1 mg/kg, ip) before each METH injection led to significant attenuations of both hyperthermia and METH adverse effects on the rat performance in the MWM task. Conclusion: The results revealed that pretreatment with the opiate antagonist naloxone could prevent METH adverse effects on body temperature and memory performance. It seems that the opioidergic system and hyperthermia may, at least partially, be involved in METH effects on spatial memory. [GMJ. 2019;8:e1182]

Implications of alpha-synuclein nitration at tyrosine 39 in methamphetamine-induced neurotoxicity in vitro and in vivo.

Methamphetamine is an amphetamine-type psychostimulant that can damage dopaminergic neurons and cause characteristic pathological changes similar to neurodegenerative diseases such as Parkinson's disease. However, its specific mechanism of action is still unclear. In the present study, we established a Parkinson's disease pathology model by exposing SH-SY5Y cells and C57BL/6J mice to methamphetamine. In vitro experiments were performed with 0, 0.5, 1.0, 1.5, 2.0 or 2.5 mM methamphetamine for 24 hours or 2.0 mM methamphetamine for 0-, 2-, 4-, 8-, 16-, and 24-hour culture of SH-SY5Y cells. Additional experimental groups of SH-SY5Y cells were administered a nitric oxide inhibitor, 0.1 mM N-nitro-L-arginine, 1 hour before exposure to 2.0 mM methamphetamine for 24 hours. In vivo experiments: C57BL/6J mice were intraperitoneally injected with N-nitro-L-arginine (8 mg/kg), eight times, at intervals of 12 hours. Methamphetamine 15 mg/kg was intraperitoneally injected eight times, at intervals of 12 hours, but 0.5-hour after each N-nitro-L-arginine injection in the combined group. Western blot assay was used to determine the expression of nitric oxide synthase, α-synuclein (α-Syn), 5G4, nitrated α-synuclein at the residue Tyr39 (nT39 α-Syn), cleaved caspase-3, and cleaved poly ADP-ribose polymerase (PARP) in cells and mouse brain tissue. Immunofluorescence staining was conducted to measure the positive reaction of NeuN, nT39 α-Syn and 5G4. Enzyme linked immunosorbent assay was performed to determine the dopamine levels in the mouse brain. After methamphetamine exposure, α-Syn expression increased; the aggregation of α-Syn 5G4 increased; nT39 α-Syn, nitric oxide synthase, cleaved caspase-3, and cleaved PARP expression increased in the cultures of SH-SY5Y cells and in the brains of C57BL/6J mice; and dopamine levels were reduced in the mouse brain. These changes were markedly reduced when N-nitro-L-arginine was administered with methamphetamine in both SH-SY5Y cells and C57BL/6J mice. These results suggest that nT39 α-Syn aggregation is involved in methamphetamine neurotoxicity.

Hydrogen Sulfide Protects Hippocampal Neurons Against Methamphetamine Neurotoxicity Via Inhibition of Apoptosis and Neuroinflammation.

Methamphetamine (METH) known as a highly neurotoxic compound associated with irreversible brain cell damage that results in neurological and psychiatric abnormalities. The mechanisms of METH intoxication mainly involve intraneuronal events including oxidative stress, excitotoxicity, and dopamine oxidation. Based on recent studies, H2S can protect neurons through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Therefore, we aimed to study the effects of protection of H2S against METH neurotoxicity. The 72 male Wistar rats were randomly allocated into six groups: control (n, 12), H2S (n, 12), METH (n, 12), METH + H2S 1mg/kg (n, 12), METH + H2S 5mg/kg (n, 12), and METH + H2S 10mg/kg (n, 12) groups, (NaHS as a H2S donor; 1, 5, 10mg/kg). METH neurotoxicity was induced by 40mg/kg of METH in four intraperitoneal (IP) injections (e.g., 4 × 10mg/kgq. 2h, IP). NaHS was administered at 30min, 24h, and 48h after the final injection of METH. Seven days after METH injection, the brains were removed for biochemical assessments, glial fibrillary acidic protein (GFAP), and caspase-3 immunohistochemistry staining. H2S treatment could significantly increase both superoxide dismutase and glutathione (P < 0.01), and a reduction was observed in malondialdehyde (P < 0.05) and TNF-α (P < 0.01) versus the METH group. Moreover, H2S could significantly decrease caspase-3 and GFAP-positive cells in the CA1 region of the hippocampus (P< 0.01) compared to the METH group. According to the findings, H2S makes significant neuroprotective impacts on METH neurotoxicity due to its antioxidant and anti-inflammatory activities.

Crocin Inhibits Apoptosis and Astrogliosis of Hippocampus Neurons Against Methamphetamine Neurotoxicity via Antioxidant and Anti-inflammatory Mechanisms.

Methamphetamine (METH) is a stimulant drug, which can cause neurotoxicity and increase the risk of neurodegenerative disorders. The mechanisms of acute METH intoxication comprise intra-neuronal events including oxidative stress, dopamine oxidation, and excitotoxicity. According to recent studies, crocin protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic compound. Accordingly, this study aimed to determine if crocin can protect against METH-induced neurotoxicity. Seventy-two male Wistar rats that weighed 260-300g were randomly allocated to six groups of control (n = 12), crocin 90mg/kg group (n = 12), METH (n = 12), METH + crocin 30mg/kg (n = 12), METH + crocin 60mg/kg (n = 12), and METH + crocin 90mg/kg (n = 12). METH neurotoxicity was induced by 40mg/kg of METH in four injections (e.g., 4 × 10mg/kg q. 2h, IP). Crocin was intraperitoneally (IP) injected at 30min, 24h, and 48h after the final injection of METH. Seven days after METH injection, the rats' brains were removed for biochemical assessment using the ELISA technique, and immunohistochemistry staining was used for caspase-3 and glial fibrillary acidic protein (GFAP) detection. Crocin treatment could significantly increase superoxide dismutase (P < 0.05) and glutathione (P < 0.01) levels and reduce malondialdehyde and TNF-α in comparison with the METH group (P < 0.05). Moreover, crocin could significantly decline the level of caspase-3 and GFAP-positive cells in the CA1 region (P < 0.01). According to the results, crocin exerts neuroprotective effects on METH neurotoxicity via the inhibition of apoptosis and neuroinflammation.

Dissociation between hypothermia and neurotoxicity caused by mephedrone and methcathinone in TPH2 knockout mice.

Mephedrone is a commonly abused constituent of "bath salts" and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear. Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice. The hypothermia induced by mephedrone and methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs. Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.

The Main Molecular Mechanisms Underlying Methamphetamine- Induced Neurotoxicity and Implications for Pharmacological Treatment.

Methamphetamine (METH) is a popular new-type psychostimulant drug with complicated neurotoxicity. In spite of mounting evidence on METH-induced damage of neural cell, the accurate mechanism of toxic effect of the drug on central nervous system (CNS) has not yet been completely deciphered. Besides, effective treatment strategies toward METH neurotoxicity remain scarce and more efficacious drugs are to be developed. In this review, we summarize cellular and molecular bases that might contribute to METH-elicited neurotoxicity, which mainly include oxidative stress, excitotoxicity, and neuroinflammation. We also discuss some drugs that protect neural cells suffering from METH-induced neurotoxic consequences. We hope more in-depth investigations of exact details that how METH produces toxicity in CNS could be carried out in future and the development of new drugs as natural compounds and immunotherapies, including clinic trials, are expected.