Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease

Cerro, Patricia Del; Alquézar, Carolina; González-Naranjo, Pedro; Pérez, Concepción; Carro, Eva; Páez, Juan A.; Campillo, Nuria E.; Martín-Requero, Ángeles

doi:10.1007/s40263-018-0515-7

Cited by 6 publications

(5 citation statements)

References 68 publications

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“…During the last decade, an accumulated body of evidence demonstrated that targeting CB2 receptors might serve as a promising therapeutic approach for Alzheimer's and other neurodegenerative diseases, as they are present in dendritic cells, neuronal cells, and microglia . Furthermore, the stimulation of CB2 receptors is generally known to have an anti‐inflammatory effect or may enhance tissue damage in some conditions .…”

Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

“…167 During the last decade, an accumulated body of evidence demonstrated that targeting CB2 receptors might serve as a promising therapeutic approach for Alzheimer's and other neurodegenerative diseases, as they are present in dendritic cells, neuronal cells, and microglia. 168 Furthermore, the stimulation of CB2 receptors is generally known to have an anti-inflammatory effect or may enhance tissue damage in some conditions. 169 It should be mentioned that the expression levels of CB2 receptors are dictated by Aβ42 levels and plaque accumulation, suggesting the stimulation of CB2 receptor expression by these pathogenic events.…”

Section: Cannabinoid Type 2 Receptor Agonistsmentioning

confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

208

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

Section: Cannabinoid Type 2 Receptor Agonistsmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

208

175

View full text Add to dashboard Cite

show abstract

“…Experiments utilizing the MWM and NOR tests [46,47,49,51] supported this correlation. Notably, a decrease in pro-inflammatory cytokines such as TNF-a, IL-1β and COX-2, and apoptotic enzymes such as caspase-3, was observed [47,51], further supported by [48], who found that PGN33 reduced the death rate of Aβ-challenged neuroblastoma cells. These findings suggest that CB2R agonists possess anti-inflammatory and immunomodulatory properties possibly via suppression of the TLR4/NF-κB p65 pathway [49].…”

Section: Discussionmentioning

confidence: 61%

“…Del Cerro et al [48] demonstrated the effectiveness of the innovative CB2R agonist, PGN33 (Scheme 2), in influencing the viability of lymphoblasts isolated from late-onset AD patients. PGN33 administration at varying doses (2.5nM, 5nM, 7.5nM, 10nM) dose-dependently decreased the viability of NA-lymphoblasts, limiting their uncontrolled proliferation with a potency similar to that of the agonist JWH-133.…”

Section: Selective Agonists Of Cannabinoid Receptor 2 (Cb2r)mentioning

confidence: 99%

A Comprehensive Exploration of the Multifaceted Neuroprotective Role of Cannabinoids in Alzheimer's Disease Across a Decade of Research

Tyrakis,

Agridi,

Kourti

2024

Preprint

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Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests through dysregulation of brain function and subsequent loss of bodily control, attributed to β-amyloid plaque deposition and TAU protein hyperphosphorylation and aggregation, leading to neuronal death. Concurrently, similar cannabinoids to the ones derived from Cannabis sativa are present in the endocannabinoid system, acting through receptors CB1R and CB2R and other related receptors such as Trpv-1 and GPR-55, and are being extensively investigated for AD therapy. Given the limited efficacy and adverse effects of current available treatments, alternative approaches are crucial. Therefore, this review aims to identify effective natural and synthetic cannabinoids and elucidate their beneficial actions for AD treatment. PubMed and Scopus databases were queried (2014–2024) using keywords such as "Alzheimer's disease" and "cannabinoids". The majority of natural (THC, CBD, AEA, etc.) and synthetic (JWH-133, WIN55,212-2, CP55-940, etc.) cannabinoids included, showed promise in improving memory, cognition, and behavioral symptoms, potentially via pathways involving antioxidant effects of selective CB1R agonists (such as the BDNF/TrkB/Akt pathway) and immunomodulatory effects of selective CB2R agonists (TLR4/NF-κB p65 pathway). Combining anticholinesterase properties with cannabinoid moiety may enhance therapeutic responses, addressing cholinergic deficits of AD brains. Thus, the positive outcomes of the majority of studies discussed supports further advancing cannabinoids in clinical trials for AD treatment.

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“…These human cell lines arise from peripheral B lymphocytes infected in vitro with the Epstein–Barr virus; a process that immortalizes them [29]. Some studies have already shown alterations in the cell cycle, proliferative activity and Aβ processing, as well as higher oxidative stress in AD than control-derived LCLs [30,31,32,33,34,35,36,37,38,39].…”

Section: Introductionmentioning

confidence: 99%

Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer’s Disease Patients

et al. 2019

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Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer’s disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD.

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Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease

Abstract: Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.

Cited by 6 publications

References 68 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

A Comprehensive Exploration of the Multifaceted Neuroprotective Role of Cannabinoids in Alzheimer's Disease Across a Decade of Research

Role of Resveratrol and Selenium on Oxidative Stress and Expression of Antioxidant and Anti-Aging Genes in Immortalized Lymphocytes from Alzheimer’s Disease Patients

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