Interaction between cannabinoid and nucleotide systems as a new mechanism of signaling in retinal cell death

Hércules R. Freitas; Ricardo A. M. Reis; Ana L. M. Ventura; Guilherme R. Fran?a

doi:10.4103/1673-5374.262585

摘要：Nervous system emerges from complex signaling interactions where extrinsic (neurotransmitters and trophic factors, among others) and intrinsic factors (transcription factors) interplay in the developing tissue to control gene activity promoting chron-ic changes in cell genesis, migration, differentiation and death. The retinal microenvironment is regulated by a broad variety of chemicals, including endocannabinoids and nucleotides that mod-ulate embryonic progenitor-neuron-Müller glia signaling in very early developing or pathophysiological conditions. Accumulated evidence demonstrate the presence of a functional cannabinoid system in this tissue, with many retina cell types expressing canna-binoid CB1 and/or CB2 receptors, the two main ligands N-arachi-donoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) and enzymes that generate N-acyl phosphatidylethanolamine phospholipase, and diacylglycerol lipase (DAGL) and degrade fatty acid amide hydrolase, monoacylglycerol lipase (MAGL) and cyclooxygenase-2 endocannabinoids (Kokona et al., 2016). As in other areas of the central nervous system, cannabinoids seem to regulate neurotransmission in the retina by inhibiting the release of transmitters such as dopamine, norepinephrine, γ-aminobutyric acid and glutamate. They also play an important role in retinal cir-cuitry and in scotopic vision by modulating Ca2+ and K+ channels in bipolar cells and photoreceptors. Moreover, under pathological conditions, cannabinoids seem to induce neuroprotection in this tissue (Kokona et al., 2016). Albeit these protective effects, howev-er, recent data are implicating cannabinoid receptors in cell death in the retina, both in the early developing (Freitas et al., 2019) and diseased tissue (Matias et al., 2006; El-Remessy et al., 2011; Chen et al., 2018).