Protective effect of melatonin against metabolic disorders and neuropsychiatric injuries in type 2 diabetes mellitus mice.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia and progressive cognitive dysfunction, and our clinical investigation revealed that the plasma concentration of melatonin (Mlt) decreased and was closely related to cognition in T2DM patients. However, although many studies have suggested that Mlt has a certain protective effect on glucose and lipid metabolism disorders and neuropsychiatric injury, the underlying mechanism of Mlt against T2DM-related metabolic and cognitive impairments remains unclear. PURPOSE: The aim of the present study was to investigate the therapeutic effect of Mlt on metabolic disorders and Alzheimer's disease (AD)-like neuropsychiatric injuries in T2DM mice and to explore the possible underlying molecular mechanism involved. METHODS: A T2DM mouse model was established by a combination of a high-fat diet (HFD) and streptozotocin (STZ, 100 mg/kg, i.p.), and Mlt (5, 10 or 20 mg/kg) was intragastrically administered for six consecutive weeks. The serum levels of glycolipid metabolism indicators were measured, behavioral performance was tested, and the protein expression of key molecules involved in the regulation of synaptic plasticity, circadian rhythms, and neuroinflammation in the hippocampus was detected. Moreover, the fluorescence intensities of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA-1), amyloid ß-protein (Aß) and phosphorylated Tau (p-Tau) in the hippocampus were also observed. RESULTS: Treatment with Mlt not only improved T2DM-related metabolic disorders, as indicated by increased serum concentrations of fasting blood glucose (FBG), glycosylated hemoglobin (HbAlc), insulin (INS), total cholesterol (TC) and triglyceride (TG), improved glucose tolerance and liver and pancreas function but also alleviated AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, as indicated by decreased immobility time in the tail suspension test (TST) and forced swimming test (FST), increased preference indices of novel objects or novel arms in the novel object recognition test (NOR) and Y-maze test (Y-maze), and improved platform positioning capability in the Morris water maze (MWM) test. Moreover, treatment with Mlt also improved the hyperactivation of astrocytes and microglia in the hippocampus of mice, accompanied by reduced expression of interleukin 1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), Aß, and p-Tau and increased expression of brain-derived neurotrophic factor (BDNF), Synapsin I, Synaptotagmin I, melatonin receptor 1B (MT1B), brain muscle arnt-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period 2 (Per2), and cryptochrome 2 (Cry2). CONCLUSION: Mlt alleviated T2DM-related metabolic disorders and AD-like neuropsychiatric injuries in a HFD/STZ-induced mouse model, possibly through a mechanism involving the regulation of glial activation and associated neuroinflammation and the balancing of synaptic plasticity and circadian rhythms in the hippocampus.

Differential toxic and antiepileptic features of Vigabatrin raceme and its enantiomers.

BACKGROUND: The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. METHODS: The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/ß-catenin/GSK 3ß signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. RESULT: The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/ß-catenin/GSK 3ß signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. CONCLUSION: S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.

Melatonin protects HT-22 cells against palmitic acid-induced glucolipid metabolic dysfunction and cell injuries: Involved in the regulation of synaptic plasticity and circadian rhythms.

Melatonin (MLT) is ahormonal substance reported with various pharmacological activities.Based on its effects of neuroprotection and metabolic regulation, the aim of the present study is to investigate its potential effect on palmitic acid (PA)-induced cell injuries and glucolipid metabolic dysfunction and explore the possible mechanism. Briefly, HT-22 cells were challenged with PA (0.1 mM, 24 h) and treated with MLT (10-6-10-8 mol/L). Cell proliferation, lipid accumulation and glucose consumption were detected. The protein expression of key molecular involved with the function of synaptic plasticity and circadian rhythms were measured via western blotting, and the expression of Map-2, MT1A, MT1B and Bmal1 were measured via immunofluorescence staining. The results showed that MLT could alleviate the neurotoxicity induced by PA, as indicated by the increased cell proliferation, enhanced fluorescence intensity of Map-2, and decreased lipid deposition and insulin resistance. Moreover, treatment of MLT could reverse the imbalanced expression of p-Akt, p-ERK, Synapsin I, Synaptotagmin I, BDNF, MT1B, Bmal1, and Clock in PA-induced HT-22 cells. These results suggested a remarkably neuroprotective effect of MLT against PA-induced cell injury and glucolipid metabolic dysfunction, the mechanism of which might be involved in the regulation of synaptic plasticity and circadian rhythms.

Role of Bmal1 in Type 2 Diabetes Mellitus-Related Glycolipid Metabolic Disorder and Neuropsychiatric Injury: Involved in the Regulation of Synaptic Plasticity and Circadian Rhythms.

Increasing data suggest a crucial role of circadian rhythm in regulating metabolic and neurological diseases, and Bmal1 is regarded as a key regulator of circadian transcription. The aim of this study is to investigate the role of Bmal1 in the disruption of circadian rhythm and neuropsychiatric injuries in type 2 diabetes mellitus (T2DM). A T2DM model was induced by the combination of high-fat-diet (HFD) and streptozotocin (STZ) in vivo or HT-22 cells challenged with palmitic-acid (PA) in vitro. The glucolipid metabolism indicators, behavioral performance, and expression of synaptic plasticity proteins and circadian rhythm-related proteins were detected. These changes were also observed after interference of Bmal1 expression via overexpressed plasmid or small interfering RNAs in vitro. The results showed that HFD/STZ could induce T2DM-like glycolipid metabolic turmoil and abnormal neuropsychiatric behaviors in mice, as indicated by the increased concentrations of fasting blood-glucose (FBG), HbA1c and lipids, the impaired glucose tolerance, and the decreased preference index of novel object or novel arm in the novel object recognition test (NOR) and Y-maze test (Y-maze). Consistently, the protein expression of synaptic plasticity proteins and circadian rhythm-related proteins and the positive fluorescence intensity of MT1B and Bmal1 were decreased in the hippocampus of HFD/STZ-induced mice or PA-challenged HT-22 cells. Furthermore, overexpression of Bmal1 could improve the PA-induced lipid metabolic dysfunction and increase the decreased expressions of synaptic plasticity proteins and circadian rhythm-related proteins, and vice versa. These results suggested a crucial role of Bmal1 in T2DM-related glycolipid metabolic disorder and neuropsychiatric injury, which mechanism might be involved in the regulation of synaptic plasticity and circadian rhythms.