Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions

Abstract

In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion. Cannabinoids are able to neutralize free radicals and modulate the production of reactive oxygen species and the activity of antioxidative systems acting on CB1 and CB2 cannabinoid receptors. The activation of CB1 receptors stimulates signaling pathways involved in antioxidative defense and survival (such as the phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and Nrf2 pathways) and regulates glutamatergic signaling, the activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx, and the induction of Ca2+-regulated signaling cascades, whereas the neuroprotective effects mediated by CB2 receptors are due to the suppression of microglial activation and the release of prooxidative and proinflammatory mediators. This review summarizes the main molecular mechanisms and new advances in understanding the antioxidative and neuroprotective effects of cannabinoids. Because of the plethora of possible pharmacological interventions related to oxidative stress and cannabinoid-mediated neuroprotection, future research should be directed towards a better understanding of the interplay between activated signal transduction pathways and molecular targets with the aim to improve treatment options and efficacy by targeting the endocannabinoid system.

Cannabinoids in Late Life Parkinson’s Disease and Dementia: Biological Pathways and Clinical Challenges

“…The increased reactivity of microglia and astrocytes, as well as the pro-inflammatory [ 44 ] markers TNF-α, IL-17, IFN-γ, iNOS, IL-1β, and NF-κB, are factors implicated in these diseases, where ECS modulation can be a critical pharmacological and molecular target. Furthermore, endocannabinoid modulation can prevent mitochondrial damage, facilitate homeostasis, and decrease excitotoxicity, as well as reactive oxygen species (ROS), culminating in restoring memory and cognitive function, prevalent in the diseases mentioned earlier [ 45 , 46 , 47 ]. As seen in the image ( Figure 1 ), adequate functioning of the ECS can be an essential tool in the homeostasis of inflammatory responses, in glial reactivity, in the proper functioning of mitochondrial complexes, and the control of the expression of proteins implicated in the pathophysiology of AD ( Table 1 ) and PD.…”

“…As seen in the image ( Figure 1 ), adequate functioning of the ECS can be an essential tool in the homeostasis of inflammatory responses, in glial reactivity, in the proper functioning of mitochondrial complexes, and the control of the expression of proteins implicated in the pathophysiology of AD ( Table 1 ) and PD. Furthermore, this system and its complex machinery have also participated in synaptic plasticity and neurogenesis events [ 46 ]. Both CBD and THC have potential targets for therapeutic effects on neurodegenerative diseases, since they can modulate ECS.…”

“…Small, limited trials have directly examined the effects of cannabinoid-based therapeutics on patients with dementia originating due to various underlying pathologies [ 46 ]. Most of the studies that we have available in the scientific literature on the action of cannabinoids on pathological mechanisms of dementia were observed in preclinical models—in vitro and animal.…”

Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential

“…Activation of CB1R blocks the release of various excitatory and inhibitory neurotransmitters and regulates the activity of specific ion channels [ 54 ]. In addition, binding to CB1R stimulates signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt, MAPK and Nrf2 cascades involved in antioxidative defense and survival and activates N-methyl-D-aspartate (NMDA) receptors, Ca 2+ signaling cascades and influx, thereby regulating glutamatergic signaling [ 55 ]. CB2R signaling also suppresses adenylyl cyclase, lowers cAMP levels, and decreases PKA activity [ 55 ].…”

“…In addition, binding to CB1R stimulates signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt, MAPK and Nrf2 cascades involved in antioxidative defense and survival and activates N-methyl-D-aspartate (NMDA) receptors, Ca 2+ signaling cascades and influx, thereby regulating glutamatergic signaling [ 55 ]. CB2R signaling also suppresses adenylyl cyclase, lowers cAMP levels, and decreases PKA activity [ 55 ]. However, cAMP synthesis and activation of Akt and ERK signaling pathways are stimulated by CB2R signaling, probably by regulating different adenylyl cyclase isozymes [ 54 ].…”