Authors: Irene Catalano, Francesco Mistretta
Δ9-tetrahydrocannabinol (Δ9-THC) is the major psychoactive ingredient of marijuana. The pharmacological actions of Δ9-THC result from its partial agonist activity at the cannabinoid receptor CB1, located mainly in the central nervous system, and the CB2 receptor, mainly expressed in cells of the immune system. CB1 and CB2 are pertussis toxin (PTX)-sensitive G-protein-coupled receptors.
The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG).
Marijuana possesses anti-oxidant, anti-inflammatory and neuroprotective properties. For these reasons it has been used for thousands of years as a treatment for medical conditions such as:
- Chronic pain
- Multiple sclerosis
- Seizure disorders
- Inflammatory diseases
- Neurodegenerative diseases
However, the undesirable neuropsychological and cognitive side effects greatly limit the medical use of marijuana. The major intoxicating effects of cannabis are the impairments in synaptic and cognitive function. These untoward effects are also the primary consequences of cannabis abuse.
Some of the potential adverse effects of marijuana are:
- Pulmonary effects
- Cardiovascular effects
- Neurodevelopment alterations
- Attention deficit hyper- activity disorder (ADHD)
- Withdrawal syndrome
Therapeutic aspects of cannabis and cannabinoids, 2001
Marijuana: current concepts, 2013
COX-2 Signaling, induced by Δ9-THC, causes Synaptic and Memory Impairments
COX-2 is an inducible enzyme that converts arachidonic acid to prostanoids in the brain.
The endocannabinoid 2-AG suppresses COX-2 via a CB1R-depedent mechanism in response to proinflammatory and excitotoxic insults. Surprisingly, the exogenous cannabinoid Δ9-THC increases COX-2 activity and expression, in a dose- and time-dependent manner, through the same receptor (CB1R).
CB1R is coupled to a PTX-sensitive Gi/o protein, and activation of CB1R releases Gβγ subunits from the GTPbound Gαi subunit.
COX-2 induction by Δ9-THC is mediated via Gβγ subunits, whereas COX-2 suppression by 2-AG is mediated via the Gαi subunit, suggesting that the activation of the same CB1 receptor may induce opposite biological effects.
Activation of CB1R/Gi/o either by 2-AG or Δ9-THC induces both Gαi - and Gβγ - mediated effector responses through different downstream signaling events.
In the case of COX-2 induction, the Gβγ -mediated COX-2 induction by Δ9-THC may be predominant, which may mask Gαi -mediated COX-2 suppression.
Akt, ERK, p38MAPK, and NF-kB are downstream signaling of Gβγ and Δ9-THC induces phosphorylation of these signaling molecules. NF-kB is a transcription factor regulating expression of genes, including the COX-2 gene. Phosphorylation of Akt, ERK, p38MAPK, and NF-kB is confirmed in the hippocampus of animals that received Δ9-THC.
COX-2 produces PGE2 which stimulates glutamate released from presynaptic nerve terminals and astroglial cells, resulting in an extracellular accumulation of glutamate. The increased extracellular glutamate may also result from the reduced uptake of glutamate by glutamate transporters because expression of these transporters is downregulated by repeated exposure to Δ9-THC. Moreover this accumulation of glutamate in the extracellular apartment by repeated Δ9-THC exposure contributes to reductions in total and surface expression of the glutamate receptors and the density of dendritic spines in the hippocampus.
Fig. Decrease in dendritic spine density by Δ9-THC is prevented by inhibition of COX-2 (NS398: inhibitor of COX-2)
It has been demonstrated that repeated in vivo exposures to Δ9-THC significantly reduced expression of GluR1, NR2A, and NR2B subunits, while NR1 and GluR2 remained unchanged.
Repeated exposures to Δ9-THC not only downregulate these GluR subunits, but also induce their internalization or endocytosis. This reduction of the AMPA and NMDA receptor subunits was prevented in WT animals that received SR, a selective CB1 antagonist, and in CB1 KO mice, indicating that the Δ9-THC induced decreases in the expression of the GluRs are mediated via the CB1R.
Thus, the elevated synaptic release of glutamate via COX-2, in Δ9-THC-exposed animals, may lead to downregulation or internalization of the GluRs as a mechanism of homeostatic plasticity (neural adaptive changes in synapses).
Moreover in vivo exposure to Δ9-THC results in decreases in CREB and its phosphorylation. The reduced phosphorylation of CREB may also be responsible for the Δ9-THC-induced down-regulation of the expression of GluRs because CREB regulates gene expression as a transcript factor.
These changes in hippocampal synapses induce hippocampal LTP (long-term potentiation) deterioration and this suggests that persistent elevation of COX-2 in the brain is detrimental to integrity of synaptic structure and plasticity. LTP deterioration translates into impairment of learning and memory function.
Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling, 2013
Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity, 2010
COX-2 Inhibition: Future Perspectives
Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons
induced by repeated Δ9-THC exposures.
Furthermore the basal phosphorylation of CREB is restored by COX-2 inhibition.
Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories.
Fig. COX inhibition by NS398 rescues decreased hippocampal LTP induced by repeated in vivo exposure to Δ9-THC
Importantly, the beneficial effects of Δ9-THC are preserved while COX-2 is inhibited.
Δ9-THC significantly elevates expression of neprilysin, an important endopeptidase for degradation of β-amyloid plaques, typical of Alzheimer’s disease. This suggests that Δ9-THC is capable of reducing amyloid β-peptide (Aβ) aggregation and neurodegeneration in an animal model of AD and that the Aβ-reducing effect is likely through elevating expression of neprilysin.
Moreover Δ9-tetrahydrocannabinol competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid β-peptide aggregation. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Aβ aggregation.
A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology, 2006
This suggests that Δ9-THC may have therapeutic potential for prevention and treatment of AD if its undesirable side effects can be eliminated by COX-2 inhibition.
Inhibition of COX-2-mediated eicosanoid production plays a major role in the anti-inflammatory effects of the endocannabinoid N-docosahexaenoylethanolamine (DHEA) in macrophages. 2015