The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Abstract

Endocannabinoids are released following brain injury and may protect against excitotoxic damage during the acute stage of injury. Brain injury also activates microglia in a secondary inflammatory phase of more widespread damage. Most drugs targeting the acute stage are not effective if administered more than 6 hours after injury. Therefore, drugs targeting microglia later in the neurodegenerative cascade are desirable. We have found that cannabinoid CB2 receptors are upregulated during the activation of microglia following brain injury. Specifically, CB2-positive cells appear in the rat brain following both hypoxia-ischemia (HI) and middle cerebral artery occlusion (MCAO). This may regulate post-injury microglial activation and inflammatory functions. In this paper we review in vivo and in vitro studies of CB2 receptors in microglia, including our results on CB2 expression post-injury. Taken together, studies show that CB2 is upregulated during a process in which microglia become primed to proliferate, and then become fully reactive. In addition, CB2 activation appears to prevent or decrease microglial activation. In a rodent model of Alzheimer's disease microglial activation was completely prevented by administration of a selective CB2 agonist. The presence of CB2 receptors in microglia in the human Alzheimer's diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies.

Cannabinoid Ester Constituents from High-PotencyCannabis sativa

“…The CB1 receptor, uniquely recognized by cannabinoids, is found in brain and peripheral tissue of the central nervous system (CNS), 23 while the CB2 receptor is primarily found outside the CNS in tissues associated with immune function. 24 The availability of high-potency marijuana on the illicit market with unprecedented Δ 9 -THC concentrations (>20% by dry weight) 25 has renewed our interest in the discovery of new constituents from C. sativa L. We herein report the isolation and structure elucidation of 11 new esters from a high-potency variety of cannabis. These esters are β-fenchyl Δ 9 -tetrahydrocannabinolate (1), epi-bornyl Δ 9 -tetrahydrocannabinolate (2), α-terpenyl Δ 9 -tetrahydrocannabinolate (3), 4-terpenyl Δ 9 -tetrahydrocannabinolate (4), α-cadinyl Δ 9 -tetrahydrocannabinolate (5), γ-eudesmyl Δ 9 -tetrahydrocannabinolate (6), γ-eudesmyl cannabigerolate (7), 4-terpenyl cannabinolate (8), bornyl Δ 9 -tetrahydrocannabinolate (9), α-fenchyl Δ 9 -tetrahydrocannabinolate (10), and α-cadinyl cannabigerolate (11).…”

Development and Evaluation of Novel PET Tracers for Imaging Cannabinoid Receptor Type 2 in Brain

“…For instance in the brain of Alzheimer patients where activated microglia cluster at β-amyloid plaques. [2][3][4][5] CB2 increase is also reported for the rat chronic lesion model of Huntington's disease, especially in the striatum. [6] Furthermore, both hypoxia-ischemia and middle cerebral artery occlusion induced an up-regulation in the expression of CB2 in proliferating microglia in rat brain.…”

Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model

“…An increase in CB 2 expression has previously been exclusively described in models involving MCAO [4,13,15]. Ashton et al showed clusters of CB 2 and CD45 + microglia/ macrophages via immunohistochemistry and Western blot in the ischaemic penumbra at 3 days after MCAO until at least 7 days after surgery [15].…”

“…Most of the available drugs target the penumbra, which has been defined as brain tissue that is functionally impaired but potentially salvageable if treated in time [3]. Unfortunately, there is just a small time window of opportunity so that most of the drugs that work in the acute phase are ineffective if administered more than 6 h after cerebral ischaemia [4]. Hence, elaborate research and drug development for stroke are indispensable.…”