Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ1-42 peptide in rat hippocampal neurons

Elmazoğlu, Zübeyir; Rangel-López, Edgar; Medina-Campos, Omar Noel; Pedraza‐Chaverrí, José; Túnez, Isaac; Aschner, Michael; Santamarı́a, Abel; Karasu, Çi̇men

doi:10.1016/j.neuint.2020.104817

Cited by 31 publications

(16 citation statements)

References 72 publications

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“…The irreversible covalent URB597 promoted the increase in endocannabinoid anandamide by inhibiting FAAH activity [ 145 , 146 ]. Furthermore, URB597 efficiently suppressed glutamate Aβ42-induced toxicity in primary hippocampal neurons and stimulated the mitochondrial membrane potential [ 147 ]. URB597 treatment is associated with the reduction in interleukin (IL)-1β, tumor necrosis factor-α (TNFα) expression, and restoration of long-term potentiation in aged rats [ 148 ].…”

Section: Cannabinoids and Endocannabinoid Systemsmentioning

confidence: 99%

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Abate

Uberti

Tambaro

2021

Biology

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Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.

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Section: Cannabinoids and Endocannabinoid Systemsmentioning

confidence: 99%

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Abate

Uberti

Tambaro

2021

Biology

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“…AD neuron viability was detected using MTT assay [65]. AD hippocampal neurons (5×10 5 cells/mL) were seeded into 96-well plates with 5 × 10 5 /mL, and AGING intervened according to the experimental groups.…”

Section: -(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium Bromide (M...mentioning

confidence: 99%

Mesenchymal stem cells-derived extracellular vesicles ameliorate Alzheimer’s disease in rat models via the microRNA-29c-3p/BACE1 axis and the Wnt/β-catenin pathway

Sha¹,

Shen²,

Cao³

et al. 2021

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Currently, Alzheimer's disease (AD) cannot be treated effectively. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) (MSC-EVs) exhibit therapeutic effects on many diseases. This study investigated the mechanism of bone marrow MSC-EVs (BM-MSC-EVs) in a rat model of AD. The cognitive function, amyloid-β (Aβ) plaques, Aβ deposition areas and levels of Aβ1-42, Aβ decomposition-related factors (NEP and IDE), and inflammatory cytokines in BM-MSC-EVs-treated AD rats were measured. The effect of BM-MSC-EVs was studied in AD neuron model. microRNA (miR)-29c-3p and BACE1 expression, as well as levels of Wnt/β-catenin pathway-related factors in AD and EVs-treated AD models were detected. miR-29c-3p relationship with BACE1 was predicted and confirmed. miR-29c-3p and BACE1 were interfered to verify the mechanism of EVs in AD. The Wnt/β-catenin pathway inhibitor DKK1 was further added to EVs-treated AD neurons. BM-MSC-EVs showed therapeutic effects on AD rats and neurons. BM-MSC-EVs carried miR-29c-3p into AD neurons. miR-29c-3p targeted BACE1. Silencing miR-29c-3p in BM-MSCs reduced BM-MSC-EV therapeutic effect on AD, which was reversed after BACE1 knockdown. miR-29c-3p targeted BACE1 and activated the Wnt/β-catenin pathway, and the Wnt/β-catenin pathway inhibition impaired EV therapeutic effects on AD. We highlighted that BM-MSC-EVs delivered miR-29c-3p to neurons to inhibit BACE1 expression and activate the Wnt/β-catenin pathway, thereby playing a therapeutic role in AD. This study may provide a novel perspective for elucidating the mechanism of MSCs in the treatment of AD.

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“…Preclinical studies with MJN110 ( Figure 2 ) showed that MAGL inhibitors’ administration is associated with reduced food intake in rats [ 114 ]. Taking into account the above-mentioned effects, and also that systemic oxidative stress, which is reported to possess a negative impact on lipids, proteins and endothelial function [ 115 ], is decreased by 2-AG [ 116 ], inhibiting MAGL may prove a useful strategy for the treatment of obesity and its comorbidities.…”

Section: Potential Therapeutic Applications Of Magl Inhibitionmentioning

confidence: 99%

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

et al. 2021

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Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

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Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ1-42 peptide in rat hippocampal neurons

Cited by 31 publications

References 72 publications

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

Mesenchymal stem cells-derived extracellular vesicles ameliorate Alzheimer’s disease in rat models via the microRNA-29c-3p/BACE1 axis and the Wnt/β-catenin pathway

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

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