Rarily lowered IOP within a welltolerated manner in most individuals, whereas 40 mg of CBD, a nonpsychotropic pCB, created a transient raise of IOP [98]. Within this context, the usage of animal models pretreated together with the CB1 antagonist SR141716A allowed to demonstrate that THC and other pCBs can decrease IOP by straight activating ocular CB1 [99], as well as by modulating production and drainage of aqueous humor [99, 100]. On the other hand, independent research have shown that Narachidonoylglycine (NAGly) and abnormal cannabidiol (AbnCBD), two agonists of GPR18 (a not too long ago deorphanized G proteincoupled receptor related to eCBbinding targets), are in a position to lessen IOP in a murine model of disease [101]. Several added preclinical and clinical research have interrogated the effects of THC and CBD on IOP modulation, establishing valuable effects in individuals with glaucoma although it really is just a relief of symptoms and, furthermore, tolerance, quick duration of those compounds too as peripheral and CNS sideeffects did not enable their use in ophthalmic clinic [98, 102107]. Additional not too long ago, scientific interest towards these compounds has been focused on their neuroprotective action that benefits inside a higher longterm efficacy in treating glaucoma and retinal neurodegenerative diseases. In this context, unique animal models of ocular ailments have represented suitable tools to dissect the mechanisms by which pCBs and/or eCBs can exert neuroprotective effects: NMDAinduced retinal cellFig. (1). Inside the eye. Schematic representation with the human eye with an overview of ECS distribution. AEA is manly synthesized by NAPEPLD, whereas DAGL is the most significant enzyme for the biosynthesis of 2AG. AEA and 2AG L-838417 manufacturer signalling pathways are terminated by enzymatic hydrolysis, mediated primarily by the serine hydrolases FAAH and MAGL, respectively. Within the crosssection, the presence of ECS element in different layers on the retina is shown. Abbreviations: AEA, anandamide; 2AG, 2arachidonoylglycerol; NAPEPLD, Narachidonoylphosphatidylethanolaminespecific phospholipase D; DAGL, diacylglycerol lipase; FAAH; fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; CBR, cannabinoid receptors; GPR55, G proteincoupled receptor 55; TRPV1, transient receptor 2-Chloroprocaine hydrochloride hydrochloride prospective vanilloid variety 1; GLC, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; IS/OS photoreceptor layer; RPE, retinal pigment epithelium.962 Current Neuropharmacology, 2018, Vol. 16, No.Rapino et al.degeneration, AMPA (amino3hydroxy5methyl4isoxazolepropionic acid)induced or lightinduced transient ischemia, IOPreperfusion (glaucoma) along with the streptozotocin (STZ)induced diabetic retinopathy [35, 38, 39, 41, 43, 105, 108110]. Incidentally, it should be noted that an excessive extracellular glutamate stimulates NMDA receptors involved in retinal neuronal cell death, an occasion that is common to glaucoma, retinal ischemia, and diabetic retinopathy. For instance, in a NMDA excitotoxic rat model, THC and CBD had been located to protect the retina in a CB1/CB2independent manner, by decreasing peroyxnitrite levels and oxidative stressrelated substances in neurons from the INL and GCL [108]. Regularly, independent research underlined the antioxidant capacity of THC (and other pCBs) as a key function to supply retinal neuroprotection (for a complete evaluation see [44]). In DR, retinal vascular dysfunction is linked to enhanced production of inflammatory mediators, su.