Alzheimer's disease

Cannabinoids: pre-clinical studies on anti-inflammatory and neuroprotective effects in Alzheimer’s disease

 

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

https://neurologybuzz.com/

June 25, 2018

Introduction

Alzheimer’s disease is not a natural progression of senescence. It is a neurological disorder involving deposition of beta amyloid peptides in senile plaques and accumulation of amyloid precursor proteins within the cerebrum particularly in areas affecting memory and cognition. Current pharmaceutic agents at best can only slow the progression of this disorder. There is no cure. Because it not a devastating illness in that it does not decrease the longevity per se, nonetheless, it is devastating to the patient and family members around him or her.

With the advent of cannabinoids into the pharmaceutic fold, attention is turning towards medical value outside its well-known repertory including anti-inflammatory and neuroprotective properties. Can cannabinoids slow the inflammatory process that is involved in this neurodegenerative condition? This seeks to explore mechanisms by which cannabinoids may play a role in ameliorating the clinical effects seen in Alzheimer’s disease.

Endocannabinoid system

As an overview, the endocannabinoids system is found naturally within the body consisting of endocannabinoids, enzymes and receptors. There are 2 receptors the CB1 receptor which is concentrated in the nervous system and found to a lesser extent in other organ systems and the CB2 receptor which is found mostly in the immune system and in other systems.  Anandamide is an endocannabinoid that exerts its actions on the CB1 receptor, while di-arachidonoylglycerol has a low affinity for the CB1 receptor and interacts with the TPRV or transient receptor potential channels of the vanilloid subtype and the G-coupled receptor family.

Within the cannabis sativa plant are 2 most well-studied phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The CB1 receptor is where delta-9-tetrahydrocannabinol (THC), a mimetic of Anandamide, interacts and can cause psychoactive effects. Cannabidiol is a mimetic of di-arachidonoylglyerol with a lower affinity to the CB1 receptor where 100 times the amount of CBD is required to achieve the same psychoactivity as THC. When CBD and THC are combined there are less side effects since the CBD acts as a non-competitive allosteric modulator at the  CB1 receptor. When the 2 are combined there is an effect that is increased together compared to when each cannabinoid is taken alone, where the effect is significantly much different. The presence of CBD offsets side effects of THC. Common side effects include agitation, hyperactivity and paranoia.

CAA11F12-A957-4FAF-B74D-6C7D2CE6E613

Mechanisms

Senile plaques are found to express CB1 and CB2 receptors within the brain in addition to microglial activation markers. The neurons are rich in CB1 receptors but seem to be greatly reduced in microglial activated areas. CB1 receptor expression and G-related coupled protein are reduced in brains with Alzheimer’s disease. Nitration of proteins are enhanced especially in CB1 and CB2 proteins in Alzheimer’s diseased brains. Adding synthetic cannabinoid WIN55-212-2 to rats caused an inhibition of microglial activation and neuron marker loss. Cannabinoids were found to ameliorate neurotoxicity caused by microglial activation (1).

Another study demonstrates the role of cannabinoids on inflammation in the mouse model using synthetic cannabinoids JWH-133 and WIN55.212-2. Cognition and inflammation were studied. FDG uptake on PET scan  was used to assess areas of metabolic uptake. The amyloid precursor protein mice showed poor object recognition. After administration of the JWH compound, cognitive impairments were reversed. There was reduced FDG uptake in the hippocampal areas. No changes were seen using WIN55.212-2. Beta amyloid proteins were significantly reduced in the mice models when cannabinoids were applied. Microglia was elevated in the APP mice which was reduced after cannabinoid administration (2).

In another mouse study, CB2 receptors were at a low level found in the neurons of unmanipulated mice whereas there was a noted increase in the CB2 receptors in mice that underwent chronic inflammation in the microglia surrounding plaques. This suggests that there is an upregulation of CB2 receptors in the presence of pathological inflammation. This may be a potential target in therapeutic agents in the future (3).

In summary

These pre-clinical studies demonstrate a neuroprotective and anti-inflammatory role of cannabinoids on Alzheimer’s disease. The CB2 appears to be upregulated around activated microglial cells around plaques implying a possible therapeutic target for future treatments. While pre-clinical studies are not human trials, elucidating these mechanisms may play a role in the future therapeutic benefits of cannabinoids on Alzheimer’s disease.

https://neurologybuzz.com/
Introduction/Disclaimer

About

 

References

  1. Ramirez, B.G., Blazquez, C., del Pulgar, T.G., Guzman, M., de Ceballos, M.L. Prevention of Alzheimer’s disease pathologyby cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005, 25:1904-13
  2. Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G.,  Cuadrado, A., de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflam. 2012, 9:8
  3. Lopez, A., Aparicio, N., Pazos, M.R., Grande, M.T., Barredo-Manso, M.A., Benito-Cuesta, I., Vazquez, C., Amores, M., Ruiz-Perez, G., Garcia-Garcia, E., Beatka, M., Tolon, R.M., Dittel, B.N., Hillard, C.J., Romero, J. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflam. 2018, May, 15:158
Standard

One thought on “Cannabinoids: pre-clinical studies on anti-inflammatory and neuroprotective effects in Alzheimer’s disease

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.