Metabolic brain disease最新文献

Chronic cerebral hypoperfusion (CCH) is the second leading cause of dementia and a major contributor to vascular dementia (VaD). Among the mechanisms underlying CCH-induced cognitive decline, programmed cell death plays a pivotal role. Lytic forms of programmed cell death, including necroptosis and pyroptosis, have recently been identified as consequences of chronic inflammation. However, their precise involvement in VaD remains unclear. It has been demonstrated that piracetam has neuroprotective and cognitive-enhancing properties, potentially through anti-inflammatory and antioxidant mechanisms. Nevertheless, its effects in the context of VaD have not yet been fully investigated. This study aimed to investigate the therapeutic potential of piracetam and elucidate any underlying mechanisms. Male Wistar rats underwent bilateral common carotid artery occlusion to induce CCH. Following this procedure, the rats received either piracetam (600 mg/kg) or resveratrol (20 mg/kg) daily for 28 days. Before euthanasia, cognitive performance was assessed using the Morris water maze test. Then biochemical analyses, including Western blotting and immunohistochemistry, were performed to assess markers of oxidative stress, neuroinflammation, pyroptosis, and necroptosis. Our findings demonstrated that piracetam reduced oxidative stress, suppressed neuroinflammatory responses, enhanced superoxide dismutase activity, and provided protection against pyroptotic and necroptotic cell death. Mechanistic studies showed that piracetam activated AMP-activated protein kinase (AMPK), which in turn upregulated sirtuin 1 (SIRT-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2), leading to improved cognitive performance. In conclusion, piracetam ameliorates cognitive impairment in CCH-induced VaD by modulating oxidative damage, neuroinflammation, and inflammatory cell death, potentially through activation of the AMPK/SIRT-1/Nrf-2 signaling pathway.

Depression is a complex disorder involving neurotransmitter imbalance, oxidative stress, and inflammation of the brain tissue. Traditional antidepressants like duloxetine (Cymbalta^®) can produce side effects. Natural extracts like Coffea canephora (green coffee) and Nigella sativa (black seeds) have emerged as possible alternative therapies. The present study aims to evaluate the antidepressant efficacy of Cymbalta, green coffee, and black seeds in a reserpine-induced rat depression model. Thirty adult male albino rats were divided into five groups: (1) Control group, (2) Depression-induced group (reserpine 0.2 mg/kg for 14 days, followed by 0.1 mg/kg intraperitoneally), (3) Cymbalta-treated group (30 mg/kg orally for four weeks), (4) Green coffee-treated group (400 mg/kg orally for four weeks), and (5) Black seed-treated group (350 mg/kg orally for four weeks). Behavioral tests (FST, Y-maze), neurotransmitter (DA, 5-HT, NE), oxidative stress markers (MDA, NO, GSH), and neuroinflammatory cytokine levels (Iba-1) were analyzed. Cymbalta significantly decreased immobility time in FST and Y-maze, restored neurotransmitter balance, reduced oxidative stress, and mitigated neuroinflammation that induced by reserpine. Also, the green coffee and black seeds demonstrated antidepressant effects against the alterations induced by reserpine, the treatment with black seeds exhibiting superior neurochemical and antioxidant benefits compared with green coffee treatment. Cymbalta showed the greatest antidepressant action, but the green coffee and the black seeds presented good neuroprotective and antidepressant activities. These findings suggest that the natural compounds may serve as adjunctive therapies for depression.

Maple syrup urine disease (MSUD) is a genetic disorder of the metabolism of branched-chain amino acids (BCAAs). We investigate the effects of treatment with dietary restriction and carnitine supplementation in MSUD patients. During treatment, patients were placed on a restricted diet and received a semi-synthetic formula enriched with carnitine. Our results revealed that treated patients showed elevated levels of neurodegeneration biomarkers (BDNF and PDGF-BB), while levels of TBARS and isoprostanes, indicators of lipid oxidative damage, were significantly decreased compared to diagnostic group. We observed an increase in L-carnitine levels after treatment, which suggests a positive response to supplementation. BCAAs and branched-chain α-keto acid dehydrogenase levels were elevated at diagnosis but decreased after treatment, indicating therapeutic efficacy. Our results highlight the importance of carnitine supplementation in the treatment of MSUD patients, possibly mitigating the neurological and metabolic involvement of the disease, providing valuable insights to optimize therapy and improve clinical outcomes.

Vulnerable brain models exhibit heightened susceptibility to anesthetic neurotoxicity, with diabetic offspring warranting particular attention, yet the underlying mechanisms remain unclear. This study integrated bioinformatics and experiments to investigate the molecular basis of sevoflurane-induced neurodevelopmental toxicity in diabetic offspring. Offspring of streptozotocin-induced diabetic dams (gestational diabetes model) and control mice were exposed to sevoflurane (2.5%, 3 × 2 h, P6-P8). Hippocampal tissues underwent RNA sequencing. Bioinformatics analysis identified dysregulated pathways, followed by validation of neuronal apoptosis (TUNEL), synaptic proteins (PSD-95, Synaptophysin), and microglial activity (Iba1+). Hub genes were screened via protein-protein interaction networks. Diabetic-sevoflurane offspring showed aberrant activation of neural crest differentiation, oxidative stress/redox pathways, and microglial pathogen phagocytosis. Compare with the Control group the diabetic-sevoflurane offspring showed increased apoptosis, synaptic loss and enhanced Iba1 + microglial density. Uty, Uba1y, Ddx3y, Kdm5d, and Eif2s3y were identified as key regulators. Gestational diabetes primes microglia via Hub gene networks, amplifying sevoflurane-induced neurotoxicity. Targeting these genes may mitigate risks in diabetic offspring requiring anesthesia.Clinical trial number: Not applicable.

Obesity and diabetes are major risk factors for ischemic stroke, leading to high comorbidity and poor recovery worldwide. Current treatments are not effective in stroke patients with obesity and diabetes because of their diverse modifying pathogenesis. However, Fasudil has emerged as a promising candidate with potential neuroprotective properties. Herein, we investigated the protective role of Fasudil in ischemic stroke using a genetically obese mouse model. Ischemic stroke was induced by the Rose Bengal photothrombosis method in adult obese mice (C57BL/6J-ob/ob; B6. Cg-Lepob/J; 9-10 weeks old). Fasudil (10 mg/kg b.w.) was administered intraperitoneally at 30 min, 24 h and 48 h following stroke. The blood glucose and rotarod tests were performed, and mice were euthanized at 72 h after stroke for molecular analysis. Fasudil treatment reduced infarct volume and ipsilateral brain edema, and downregulated thioredoxin-interacting protein and NOD-like receptor pyrin domain-containing-3 inflammasome. Additionally, it attenuated oxidative stress, downregulated Rho-kinase A protein expression, and reduced the number of TUNEL-positive cells in the ipsilateral area. These protective effects of Fasudil were accompanied by improved blood-brain barrier integrity markers and reduced levels of phosphorylated JNK and P75NTR. Collectively, these findings suggest that Fasudil confers neuroprotective effects following stroke in genetically modified obese (ob/ob) mouse model, independent of glycemic modulation. This study highlights the potential of Fasudil as a therapeutic target for acute ischemic stroke in the context of obesity and metabolic dysfunction, warranting further investigation in preclinical and clinical settings, particularly in patients with obesity and diabetes.

Subjects with chronic kidney disease (CKD) are at higher risk for various neurological disorders, including dementia, depression, and sleep disturbances, all of which can influence disease progression and clinical outcomes. Cognitive impairment is often linked to renal decline, with the severity of cognitive deficits increasing in parallel with a reduction in glomerular filtration rate (GFR). For patients undergoing dialysis, the risk of moderate to severe cognitive impairment is significantly elevated. A central, unifying hypothesis proposes that the brain and kidneys share a similar microvascular architecture, making both organs highly susceptible to vascular injury. In this review, we make explicit two complementary mechanisms within this framework: (i) a common-cause model in which shared systemic risk factors (such as hypertension, diabetes, inflammation) concurrently damage renal and cerebral small vessels, and (ii) a CKD-mediated causal pathway whereby kidney dysfunction and its treatments propagate downstream neurovascular injury (uremic toxins, endothelial dysfunction and blood-brain barrier changes, anemia/hypoxia, metabolic and mineral disturbances, and dialysis-related hemodynamic stress), increasing the risk of cognitive impairment. We synthesize the current evidence on these mechanisms, outline the epidemiological patterns and clinical manifestations of cognitive decline in CKD, and discuss prevention, early diagnosis, and multidisciplinary management strategies aimed at improving outcomes in this vulnerable population.

Cholinesterase (ChE) refers to a group of enzymes that play a critical role in the hydrolysis of choline-based esters, particularly acetylcholine, a key neurotransmitter presents in the nervous system. The two types of cholinesterase are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), each with distinct functions and locations found within the body. Cholinesterase inhibitors (ChEIs) have been utilized to treat Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder characterized by memory loss, impacting on the quality of life. Many studies have highlighted the potential of alkaloids as inhibitors of cholinesterase enzymes. There are various alkaloids which have potential to treat AD with their different modes of actions. This review summarizes more than 14 well-known alkaloids possessing six-membered N-heterocycles as AChE and BuChE inhibitors, such as berberine, boldine, crytolepine, harmine, huperzine A, 6-hydroxycrinamine, nicotine, piperine, salsoline, skimmianine, trigonelline, valerianofal A, 7'-multijuguinone, and 12'-hydroxy-7'-multijuguinone, hamayne, and lycorine.

Arachidonic acid (AA) is an important omega-6 polyunsaturated fatty acid (PUFA) stored in esterified form within cell membrane phospholipids, and it is widely present in various cell types. The esterified AA on the inner surface of the cell membrane is primarily hydrolyzed by phospholipase A2 (PLA₂) into its free form. Subsequently, it is metabolized by cyclooxygenase (COXs), lipoxygenase (LOXs), and cytochrome P450 (CYP450) enzymes. The metabolites of AA include a range of bioactive mediators such as prostaglandins (PGs), epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs) and lipoxins (LXs). These metabolites play critical and diverse roles in cellular physiology and are implicated in the pathogenesis of major depressive disorder. This review delves into the molecular mechanisms by which arachidonic acid and its metabolites contribute to the development of major depressive disorder, providing new perspectives for the development of novel antidepressant therapies.

The neuroprotective effects of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) have been reported in experimental models of central nervous system (CNS) disorders due to its multi-target actions. Considering the limited efficacy of current treatments for post-traumatic stress disorder (PTSD), this study aimed to investigate the anti-PTSD-like effects of 4-PSQ and its underlying mechanisms during the early developmental stage of single prolonged stress (SPS)-induced PTSD in male and female mice. Following 4 h to the SPS exposure, mice were treated with 4-PSQ (5 mg kg^-1) or vehicle by the intragastric (i.g.) route for three days. The open field test, the elevated plus maze test, and the contextual fear conditioning were performed on days 2 and 3 of the experimental protocol. A short treatment with 4-PSQ reversed the anxiety-like phenotype and the fear memory strength induced by SPS in mice of both sexes. Elevated levels of reactive species (RS) in the cerebral cortex, hippocampus, and hypothalamus of SPS-exposed mice were attenuated by 4-PSQ. Concerning the antioxidant system, males and females exposed to SPS displayed distinct patterns of thiol non-protein (NPSH) levels and the catalase (CAT) activity in the CNS. Notably, the SPS-induced fear memory strength was found to be negatively correlated with Na⁺, K⁺-ATPase inhibition and positively correlated with AChE enhancement, underscoring the relevance of both enzymes in the pathogenesis of PTSD. The 4-PSQ treatment normalized both Na⁺, K⁺-ATPase and AChE activities. In Summary, the 4-PSQ attenuated the behavioral and sex-specific mechanisms in response to SPS and may be considered as promising molecule for PTSD treatment.