Introduction Aldose reductase ALR is the first

Introduction Aldose reductase (ALR2) is the first enzyme of the polyol pathway that catalyzes the reduction of glucose to sorbitol utilizing NADPH as a cofactor. The intracellular accumulation of sorbitol, due to increased aldose reductase activity at high blood glucose levels, such as those occurring in diabetes, has been implicated in the development of various secondary complications of diabetes such as neuropathy, nephropathy, retinopathy, and cataract, which practically are not controlled by insulin [1]. The aldose reductase inhibitors (ARIs) can prevent the reduction of glucose to sorbitol and reduce complications of diabetes [2]. The synthetic ARIs are often associated with deleterious side effects and poor penetration of target tissues such as nerve and retina [3]. Numerous natural compounds such as flavonoids, coumarins, terpenes and related aromatic compounds have been reported in the literature to have in vitro aldose reductase inhibitory activity [4,5]. Plants are a very important source of substances of high chemical diversity, many of which exert interesting pharmacological activities. Cannabis sativa L. (Cannabaceae) has been an important source of food, fiber, dietary oil and medicine for thousands of years in Europe, Asia and Africa [[6], [7], [8], [9]]. Several epidemiological studies have independently associated the cannabis use with a lower prevalence of diabetes mellitus (DM) in past and present cannabis consumers compared to non-cannabis users [10]. Cannabis plant is characterized by the presence of terpenophenolic compounds, known as cannabinoids. C. sativa chemotypes distinction, is based mainly on the content of ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol, cannabigerol, and their acidic forms tetrahydrocannabinolic SCR7 pyrazine australia (THCA), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA). The well-known psychotropic effects of ∆9-THC, have greatly limited therapeutic use of Cannabis. However, the presence in C. sativa of non-psychotropic cannabinoids could be promising for its possible use in therapy, free of the side psychotropic effects. These compounds include CBD, CBG, as well as cannabinoid acids such as CBDA and CBGA. The most promising of the non-psychotropic cannabinoids is CBD, which exerts several positive pharmacological effects that make it a highly attractive therapeutic entity in multiple disease models, [[11], [12], [13]] including diabetes [14,15] and diabetic complications [[16], [17], [18], [19]]. In this study, the inhibitory effects on aldose reductase activity by hexane extracts and their fractions from two different chemotypes of C. sativa fiber type CBD- or CBG-rich, with a content of Δ9-THC <0.2%, were evaluated in vitro. Phytochemical analyses of extracts and fractions were carried out by HPLC-DAD, 1H NMR and GC–MS methods. Molecular docking studies were performed to evaluate the interaction of non-psychotropic cannabinoids, CBD/CBDA and CBG/CBGA, with the active site of ALR2 comparing them with other known inhibitors.
Materials and methods
Results and discussion
Conclusions The Cannabis CBD- and CBG-type extracts with high content of non-psychotropic phytocannabinoids mainly as acids CBDA and CBGA showed higher ALR2 inhibitory activity than their fractions. Furthermore, the cannabinoid acids-rich fractions highlighted inhibitory activity higher than the fractions-rich in their neutral forms. The carboxylic acids have been reported among the most representative ARIs agents. However, the inhibitory activity of carboxylic acids in vivo is lower than in vitro, a finding that is likely attributable to their lower pKa and to a resultant impairment in penetrating biological membranes [33]. Drug molecules should possess a certain lipophilicity to permeate biological membranes, including biological barriers. Phytocannabinoids, are essentially hydrophobic compounds transported in the blood by lipoproteins and albumin [34]. Intracellular transporters for phytocannabinoids have not been described, however recent reports suggest that these hydrophobic compounds may be transported from the cell membrane through the aqueous milieu by soluble intracellular carriers [35]. Non-psychotropic phytocannabinoid-derived acids, for their structural features have good tissue penetration and several reports show that these compounds have interesting pharmacological activities [36,37].