Tuesday 26 July 2016

Cannabinoids Hold Promise for Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) is a neurodegenerative condition and the most common form of dementia worldwide, accounting for around 70% of dementia cases. Deposition of the amyloid-beta (A-beta) peptide in the form of amyloid plaques is one of the hallmarks of the disease, occurring early in the development of this condition. As disease progresses, degenerative changes accumulate, leading to neuronal death, oxidative damage, and neuroinflammation.

The exact pathological mechanisms that drive Alzheimer’s disease remain to be clarified and are the subject of extensive research (and debate). With the goal of further elucidating some of the processes that drive Alzheimer’s progression, new research published in the Nature Partner Journal Aging and Mechanisms of Disease studied the association between A-beta accumulation and the development of neuroinflammation, as well as possible therapeutic interventions. Their results were promising.

Does A-beta accumulation cause inflammation?

Neuroinflammation is a characteristic of the aging process and is one of the main causes of cognitive impairment. In the context of neurodegenerative diseases, inflammatory responses are further increased and contribute to the accelerated rate of cognitive decline that is observed. The increased inflammatory response found in the brain of Alzheimer’s patients has been mostly regarded as a consequence of the activation of glial cells in the brain.

This study, carried out in vitro, indicates that this may not be so: it establishes a direct link between A-beta and inflammation, demonstrating that A-beta production in cultured human central nervous system neurons leads to the synthesis of a number of proinflammatory molecules and to the activation of inflammatory pathways. Most of the proinflammatory molecules known to be excessively produced in the brain of Alzheimer’s patients were shown to also be overproduced in neurons after the induction of A-beta production.

Furthermore, these results suggest that A-beta production in neurons may induce inflammation even before it starts accumulating and forming amyloid plaques in the brain.

Are NSAIDs a bad choice for Alzheimer’s patients?

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to delay clinical features of Alzheimer’s disease, but clinical trials have never supported that idea. NSAIDs act by inhibiting a family of enzymes called cyclooxygenases (COX), which are responsible for the production of prostaglandins. Since prostaglandins can induce inflammatory responses, the inhibition of COX by NSAIDs results in decreased inflammation. Since COX-2 is known to be increased in the brain of Alzheimer’s patients, in theory, blocking the action of COX-2 using NSAIDs should be beneficial.

But the regulation of inflammation is not the only function of prostaglandins, which actually depends on the receptors they activate. As it turns out, according to this study, the prostaglandins PGE2 and PGD2 are actually neuroprotective, similarly to what has been found in ischemic stroke and in other neurodegeneration models. The increase in COX-2 production may therefore be a defense mechanism that neurons set in motion. By inhibiting this defense system, NSAIDs may actually promote further cellular damage.

This work showed that the detrimental action of A-beta can be mediated by the action of molecules produced by another enzyme called 5-lipoxygenase (5-LOX). These molecules, called leukotrienes, seem to be the ones that potentiate A-beta’s toxicity. It was shown that the inhibition of 5-LOX was able to prevent cell death, therefore holding better therapeutic potential than NSAIDs.

Cannabinoids effectively block A-beta toxicity

Interestingly, both prostaglandins and leukotrienes derive from the same molecule: arachidonic acid. And arachidonic acid is also a component of a family of endogenous cannabinoids produced in the brain.

Cannabinoids had already been studied in the context of Alzheimer’s disease, having been shown that they can reduce A-beta accumulation and improve memory. Not only endogenous cannabinoids, but also tetrahydrocannabinol (THC), the main psychoactive component of cannabis, are also known to be able to reduce inflammation.

Therefore, this study also investigated whether cannabinoids could have therapeutic potential for Alzheimer’s disease. It was shown that an endocannabinoid called arachidonoyl ethanol amide (AEA), as well as synthetic analogs to this molecule, could promote neuronal survival and block A-beta accumulation. The inhibition of the enzyme that degrades AEA was also shown to be protective.

THC was also tested in this study and the results were very promising: THC had a marked protective effect, being able to remove intraneuronal A-beta, to dramatically reduce the elevated production of damaging leukotrienes, and to block neuronal cell death.

The results of this study show that cannabinoids may indeed hold promise for the treatment of Alzheimer’s disease. It remains to be determined if similar effects will also be obtained in vivo.

References

Bayer, . (2010). Intracellular accumulation of amyloid-beta – a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease Frontiers in Aging Neuroscience DOI: 10.3389/fnagi.2010.00008

Burstein, S., & Zurier, R. (2009). Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation The AAPS Journal, 11 (1), 109-119 DOI: 10.1208/s12248-009-9084-5

Campbell, V., & Gowran, A. (2009). Alzheimer’s disease; taking the edge off with cannabinoids? British Journal of Pharmacology, 152 (5), 655-662 DOI: 10.1038/sj.bjp.0707446

Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., & Schubert, D. (2016). Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids npj Aging and Mechanisms of Disease, 2 DOI: 10.1038/npjamd.2016.12

Kim, E., Kwon, K., Park, J., Lee, S., Moon, C., & Baik, E. (2002). Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation Journal of Neuroscience Research, 70 (1), 97-107 DOI: 10.1002/jnr.10373

Martín-Moreno, A., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M., Innamorato, N., Cuadrado, A., & de Ceballos, M. (2012). Prolonged oral cannabinoid administration prevents neuroinflammation, lowers ?-amyloid levels and improves cognitive performance in Tg APP 2576 mice Journal of Neuroinflammation, 9 (1) DOI: 10.1186/1742-2094-9-8

Valera, E., Dargusch, R., Maher, P., & Schubert, D. (2013). Modulation of 5-Lipoxygenase in Proteotoxicity and Alzheimer’s Disease Journal of Neuroscience, 33 (25), 10512-10525 DOI: 10.1523/JNEUROSCI.5183-12.2013

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