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Cannabinoid Receptor Type 1 Agonist ACEA Improves Cognitive Deficit on STZ-Induced Neurotoxicity Through Apoptosis Pathway and NO Modulation

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The cannabinoid system has the ability to modulate cellular and molecular mechanisms, including excitotoxicity, oxidative stress, apoptosis, and inflammation, acting as a neuroprotective agent, by its relationship with signaling pathways associated to the control of cell proliferation, differentiation, and survival. Recent reports have raised new perspectives on the possible role of cannabinoid system in neurodegenerative diseases like Alzheimer disease’s (AD). AD is a neurodegenerative disorder characterized by the presence of amyloid plaques, neurofibrillary tangles, neuronal death, and progressive cognitive loss, which could be caused by energy metabolism impairment, changes in insulin signaling, chronic oxidative stress, neuroinflammation, Tau hyperphosphorylation, and Aβ deposition in the brain. Thus, we investigated the presumptive protective effect of the cannabinoid type 1 (CB1)-selective receptor agonist arachidonyl-2′-chloroethylamide (ACEA) against streptozotocin (STZ) exposure stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells) and in vivo model (intracerebroventricular STZ injection), experimental models of sporadic AD. Our results demonstrated that ACEA treatment reversed cognitive impairment and increased activity of Akt and ERK triggered by STZ, and increased IR expression and increased the anti-apoptotic proteins levels, Bcl-2. In the in vitro model, ACEA was able to rescue cells from STZ-triggered death and modulated the NO release by STZ. Our study has demonstrated a participation of the cannabinoid system in cellular survival, involving the CB1 receptor, which occurs by positive regulation of the anti-apoptotic proteins, suggesting the participation of this system in neurodegenerative processes. Our data suggest that the cannabinoid system is an interesting therapeutic target for the treatment of neurodegenerative diseases.

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Authors wish to thank the professor Dr. Julián Romero (Universidad Francisco de Vitoria, Madrid, Spain) for critical comments and his technical support during the process. We also thank to Dr. Maria Assunción de la Barreda Manso for her opinion and critical comments.

Financial Support

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP (grant number 2014/06372-0). T.A.V. (1279985) and F.C. (1233360) are recipients of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) fellowships.

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F.C. designed the experiments, collected, and analyzed the data and wrote the paper; T.A.V. and A.P.C. collected, analyzed, and discussed the data; A.S.T. designed the experiments, discussed the data, wrote, edited, and commented on the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Fernanda Crunfli.

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The experimental protocol was evaluated and approved by the “Ethics Committee for Animal use” of the Institute of Biomedical Sciences, University of São Paulo (Protocol no. 33/55/02) following the Brazilian Federal Law (no. 11794; 10/08/2008). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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The authors declare that they have no conflict of interest.

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Crunfli, F., Vrechi, T.A., Costa, A.P. et al. Cannabinoid Receptor Type 1 Agonist ACEA Improves Cognitive Deficit on STZ-Induced Neurotoxicity Through Apoptosis Pathway and NO Modulation. Neurotox Res 35, 516–529 (2019).

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