Background: Emerging neuroprotective strategies are being explored to preserve the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision. Methods: Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina. eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain. Results: Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. Conclusion: The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases.

Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array. Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH. Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.

The decriminalization and legalization of cannabis has paved the way for investigations into the potential of the use of phytocannabinoids (pCBs) as natural therapeutics for the treatment of human diseases. This growing interest has recently focused on rare (less abundant) pCBs that are non-psychotropic compounds, such as cannabigerol (CBG), cannabichromene (CBC), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). Notably, pCBs can act via the endocannabinoid system (ECS), which is involved in the regulation of key pathophysiological processes, and also in the skin. In this study, we used human keratinocytes (HaCaT cells) as an in vitro model that expresses all major ECS elements in order to systematically investigate the effects of CBG, CBC, THCV and CBGA. To this end, we analyzed the gene and protein expression of ECS components (receptors: CB₁, CB₂, GPR55, TRPV1 and PPARα/γ/δ; enzymes: NAPE-PLD, FAAH, DAGLα/β and MAGL) using qRT-PCR and Western blotting, along with assessments of their functionality using radioligand binding and activity assays. In addition, we quantified the content of endocannabinoid(-like) compounds (AEA, 2-AG, PEA, etc.) using UHPLC-MS/MS. Our results demonstrated that rare pCBs modulate the gene and protein expression of distinct ECS elements differently, as well as the content of endocannabinoid(-like) compounds. Notably, they all increased CB_1/2 binding, TRPV1 channel stimulation and FAAH and MAGL catalytic activity. These unprecedented observations should be considered when exploring the therapeutic potential of cannabis extracts for the treatment of human skin diseases.

Dysfunctional phenotype of microglia, the primary brain immune cells, may aggravate Alzheimer’s disease (AD) pathogenesis by releasing proinflammatory factors, such as nitric oxide (NO). The endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids increasingly recognised for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. To investigate the possible impact of chronic exposure to β-amyloid peptides (Aβ) on the microglial endocannabinoid signalling, we characterised the functional expression of the endocannabinoid system on neonatal microglia isolated from wild-type and Tg2576 mice, an AD-like model, which overexpresses Aβ peptides in the developing brain. We found that Aβ-exposed microglia produced 2-fold more 2-AG than normal microglia. Accordingly, the expression levels of diacylglycerol lipase-α (DAGLα) and monoacylglycerol lipase (MAGL), the main enzymes responsible for synthesising and hydrolysing 2-AG, respectively, were consistently modified in Tg2576 microglia. Furthermore, compared to wild-type cells, transgenic microglia basally showed increased expression of the cannabinoid 2 receptor, typically upregulated in an activated proinflammatory phenotype. Indeed, following inflammatory stimulus, Aβ-exposed microglia displayed an enhanced production of NO, which was abolished by pharmacological inhibition of DAGLα. These findings suggested that exposure to Aβ polarises microglial cells towards a pro-AD phenotype, possibly by enhancing 2-AG signalling.

Gynaecological cancers can be primary neoplasms, originating either from the reproductive tract or the products of conception, or secondary neoplasms, representative of metastatic disease. For some of these cancers, the exact causes are unknown; however, it is recognised that the precise aetiopathogeneses for most are multifactorial and include exogenous (such as diet) and endogenous factors (such as genetic predisposition), which mutually interact in a complex manner. One factor that has been recognised to be involved in the pathogenesis and progression of gynaecological cancers is the endocannabinoid system (ECS). The ECS consists of endocannabinoids (bioactive lipids), their receptors, and metabolic enzymes responsible for their synthesis and degradation. In this review, the impact of plant-derived (Cannabis species) cannabinoids and endocannabinoids on gynaecological cancers will be discussed within the context of the complexity of the proteins that bind, transport, and metabolise these compounds in reproductive and other tissues. In particular, the potential of endocannabinoids, their receptors, and metabolic enzymes as biomarkers of specific cancers, such as those of the endometrium, will be addressed. Additionally, the therapeutic potential of targeting selected elements of the ECS as new action points for the development of innovative drugs will be presented.