The Seek of Neuroprotection: Introducing Cannabinoids

Abstract

The cannabinoid system is constituted by some endogenous ligands (endocannabinoids), usually arachydonic acid derivatives, and their specific receptors. The endogenous cannabinoid system (ECS) is involved in the control of synaptic transmission, modulating memory, motivation, movement, nociception, appetite and thermoregulation. ECS also exert extraneural effects, mainly immunomodulation and vasodilation. Two cannabinoid receptors have been cloned so far: CB(1) receptors are expressed in the central nervous system (CNS) but can also be found in glial cells and in peripheral tissues; CB(1) receptors are Gi/o protein coupled receptors that modulate the activity of several plasma membrane proteins and intracellular signaling pathways. CB(2) receptors are also Gi/o protein-coupled receptors; although it is accepted that CB(2) receptors are not expressed in forebrain neurons, they have been described in activated glia. Some of the cannabinoids activate other receptors, for instance vanilloid receptors (TRPV1). Lately, the ECS is emerging as a natural system of neuroprotection. This consideration is based on some properties of cannabinoids as their vasodilatory effect, the inhibition of the release of excitotoxic amino acids and cytokines, and the modulation of oxidative stress and toxic production of nitric oxide. Such effects have been demonstrated in adult and newborn animal models of acute and chronic neurodegenerative conditions, and postulate cannabinoids as valuable neuroprotective agents. Patents related to cannabinoid receptors are also discussed.

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…About 25 % of severe cases result in lasting sequelae and about 20 % die, resulting in about 2 million babies dying or remaining severely disabled each year worldwide [58]. Immature brain show some characteristics that determine a higher vulnerability for hypoxic-ischemic (HI) damage, as well as some particular selectivity for the damage [58][59][60][61]: 1) a high metabolic rate and oxygen extraction together with immature glucose uptake mechanisms; 2) a highly developed excitotoxic system which overexpressed receptors responding faster and higher to glutamate; 3) hypersensitivity to inflammatory mediators, with a misbalance between pro-and antioxidant enzymes, differences in leukocyte-endothelial cell communication and distinct intracellular signaling within inflammatory pathways (NFκB and mitogen-activated protein kinase); 4) proapoptotic factor preponderancy because of the need for modeling the developing brain; and 5) antioxidant defenses only partially developed at birth. Therefore, excitotoxicity, inflammation, and oxidative stress constitute the triad of major factors leading to HI damage in immature brain [59].…”

Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum

“…These composite actions are likely to mediate the neuroprotective effects of BDNF (Castrén, 2004;Lu et al, 2005;Hennigan et al, 2007), as well as its complex effects on cognition and mood Martinowich et al, 2007). Signaling through cannabinoid CB 1 receptors (CB 1 Rs) is also emerging as a critical determinant in neuroprotection (Martínez-Orgado et al, 2007;Galve-Roperh et al, 2008), learning and memory (Horder et al, 2009;Puighermanal et al, 2009), and emotional control (Aso et al, 2008;Juhasz et al, 2009;Moreira et al, 2009), raising the possibility that BDNF and CB 1 Rs interact to regulate multiple functions in the brain.…”

Cannabidiol Reduces Brain Damage and Improves Functional Recovery After Acute Hypoxia-Ischemia in Newborn Pigs

“…C annabinoids (CBs) have emerged as valuable tools for reducing brain damage after hypoxia-ischemia (HI) in newborns (1). Several effects of CBs such as their antiinflammatory and antioxidant effects, their vasoactive effects, the reduction of Ca 2ϩ influx and of glutamate release, and the modulation of nuclear factor (NF)-B activity account for their observed neuroprotective action (1).…”

“…Several effects of CBs such as their antiinflammatory and antioxidant effects, their vasoactive effects, the reduction of Ca 2ϩ influx and of glutamate release, and the modulation of nuclear factor (NF)-B activity account for their observed neuroprotective action (1). Usually, CB 1 agonists have been considered the best neuroprotective CBs for both the mature (1) and immature (2) brain.…”