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.

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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/
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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
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Alzheimer's disease

Alzheimer’s Disease: Living with Alzheimer’s Disease

By Virginia Thornley, M.D., Neurologist
February 15, 2018

Introduction
Alzheimer’s disease is a neurodegenerative disorder affecting memory. It is thought to be caused by progressive loss of cells that control memory and cognition. A substance called acetylcholine is secreted which enhances memory, cognition, and attention. In Alzheimer’s disease, a destructive process occurs in the brain cells with accumulation of plaques composed of beta-amyloid. When this destruction of acetylcholine-producing cells occurs then there is less of the acetylcholine which is necessary for transmitting signals that control memory, attention, and cognition. Risk factors include the presence of certain genes such as the APOE gene.

Keeping Mentally Fit
Engaging in activities that involve the thought processes such as doing crossword puzzles, reading engaging books or novels or doing soduko puzzles may help boost the

 

13887115_10154408543428841_2788314143123562305_n (1)neural connections. The more brain cells are utilized the more their capacity is exercised. This is the reason why those in mentally rich occupations where lifelong complex decision-making skills are made, Alzheimer’s disease is not detected until later stages because the brain was constantly engaged for decades. Engaging in conversations, being social by going out and talking to people increase neural connections. Appreciating the arts, going to the theater engaging your brain will help boost neural connections.

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Talking to neighbors or even buying at the convenience store activate mental processes. Engaging in listening, comprehending and speaking during conversations and interactions also sustain rich neural connections.

Someone sitting at home all day long will perform significantly worse than someone who is actively out and about speaking and engaging. The old adage use it or you lose it rings true.

Staying healthy
It is always a good idea to stay fit and active, even more so when diseases affecting the brain are present. Diseases that affect and constrict the small blood vessels will also affect the end terminal cells.  Therefore, high blood pressure, high cholesterol and diabetes mellitus which all affect small vessels can also cause small blockages in blood flow to the brain. This does not help with Alzheimer’s disease. Consulting with a physician is helpful to ensure that any risk factors are under control.

Cues to help remember
A medicine box helps with memory. Bringing a friend or relative to doctors’ appointments helps with not forgetting medical advice. Writing a list helps with tasks that need to be done for the day. Placing medicine by the toothpaste helps with remembering to take important medications. Writing down doctors’ appointments and placing on the refrigerator in bold letters is another good idea. Little things may be remembered by using cues such as these. However, if forgetting extremely important details such as turning off the stove, leaving the water running or not locking the door at night occur, living alone is not feasible. Supervised living conditions are appropriate. Consult with a physician who can direct towards the correct resources and assistance.

Discussing long-term issues
If a loved one has been diagnosed with Alzheimer’s disease, it is a good time to get affairs in order. It is a difficult topic to discuss but it is the optimal time to formulate long-term plans, while preferences are known. If the disease is progressing such that decline is imminent resulting in greater supervision, steps to come up with long-term plans for care are beneficial.

Another subject which is difficult to broach are wishes in the event anything happens and preferences in the hospital for resuscitation. There are many families who come together during an event such as this only to sadly discover that this topic was never discussed. This results in lengthy discussions during an already trying and emotional time. Preparation for the future is key.

Consult with a neurologist
At this point in time, there are no medications that cure Alzheimer’s disease. Generally speaking, some may slow the progression depending on the severity and can enhance the availability of acetylcholine. Ongoing research continues.

https://neurologybuzz.com/

 

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