The effect of α-synuclein and Tau in methamphetamine induced neurotoxicity in vivo and in vitro

et al. 2021

Addiction Biology

Methamphetamine (METH) abuse has become a global public health problem. However, the potential mechanisms involving METH‐induced metabolic disorders have thus far remained poorly understood. Metabolomics can provide a clue for the cause of apparent changes and consequently be used to investigate the METH‐induced dysregulation of metabolite expression and the mechanism of metabolic disorder mechanism. This laboratory investigation included 80 METH abusers and 80 healthy people. The serum metabolites were detected and analysed by gas chromatography/time‐of‐flight mass spectrometry. Raw data were processed with the software MS DIAL, which includes deconvolution, peak alignment and compound identification. The data matrix was processed by univariate and multivariate analyses for significant metabolite screening with the criteria of variable importance in projection values > 1, fold change > 1.5 and the t test (p value < 0.05). Significant differences in 16 metabolites (deoxycholic acid, cholic acid, hydroxylamine, etc.) in serum were found between the METH abuse group and the control group. Energy metabolic pathways and several amino acid metabolic pathways (alanine, aspartic acid and glutamate metabolism and tryptophan metabolism) were primarily involved. Further analysis indicated that the area under the receiver operating characteristic curve (AUC) was 0.998 for these 16 metabolites. Among the metabolites, three carbohydrates (d‐ribose, cellobiose and maltotriose) had an AUC of 0.975, which were determined as potential markers of abuse. We observed metabolic disturbances in METH abusers, particularly perturbation in energy metabolism and amino acid metabolism, which can provide new insights into the search for biomarkers and the mechanisms underlying the adverse effects of METH on human health.

Section: Introductionmentioning

confidence: 99%

“…Therefore, METH has become one of the most harmful synthetic drugs in China, 3 and its long-term abuse has been a significant public health problem worldwide. 4,5 However, fewer studies have been conducted on synthetic drugs than on traditional drugs. Effective prevention and treatment measures remained remain inadequate.…”

Section: Introductionmentioning

confidence: 99%

Untargeted metabolomics analysis by gas chromatography/time‐of‐flight mass spectrometry of human serum from methamphetamine abusers

et al. 2021

Addiction Biology

“…Using positron emission tomography imaging, Volkow et al [ 33 ] found that the DAT density in striatum of METH abusers was decreased compared to those of healthy individuals. Previous studies have also found that METH treatment could reduce the expression levels of TH, DAT, and DA in laboratory animals [ 6 , 8 , 34 , 35 ]. Consistent with these studies, we duplicated the dopaminergic neurotoxic phenotype in mice after chronic METH exposure.…”

Section: Discussionmentioning

confidence: 98%

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Huang

Ding

Oxidative Medicine and Cellular Longevity

et al. 2022

Self Cite

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

“…Primary and secondary podocyte extensions are maintained by microtubules whose depolymerization may be related with observed simplification. Moreover, neuroscience research have shown that the accumulation of p-Tau in neurons may cause neuron dysfunction and neuropathology [ 39 ]. Similarly, the toxic p-Tau increasing in podocytes resembles the effect in neurons.…”

Section: Discussionmentioning

confidence: 99%

Luteolin Ameliorates Methamphetamine-Induced Podocyte Pathology by Inhibiting Tau Phosphorylation in Mice

Ding

Evidence-Based Complementary and Alternative Medicine

et al. 2022

Self Cite

Methamphetamine (METH) can cause kidney dysfunction. Luteolin is a flavonoid compound that can alleviate kidney dysfunction. We aimed to observe the renal-protective effect of luteolin on METH-induced nephropathies and to clarify the potential mechanism of action. The mice were treated with METH (1.0–20.0 mg/kg/d bodyweight) for 14 consecutive days. Morphological studies, renal function, and podocyte specific proteins were analyzed in the chronic METH model in vivo. Cultured podocytes were used to support the protective effects of luteolin on METH-induced podocyte injury. We observed increased levels of p-Tau and p-GSK3β and elevated glomerular pathology, renal dysfunction, renal fibrosis, foot process effacement, macrophage infiltration, and podocyte specific protein loss. Inhibition of GSK3β activation protected METH-induced kidney injury. Furthermore, luteolin could obliterate glomerular pathologies, inhibit podocyte protein loss, and stop p-Tau level increase. Luteolin could also abolish the METH-induced podocyte injury by inactivating GSK3β-p-Tau in cultured podocytes. These results indicate that luteolin might ameliorate methamphetamine-induced podocyte pathology through GSK3β-p-Tau axis.