Cannabinoids and Medicinal Benefits Flashcards
What is the ECS well established for?
A target for therapy of pain
What system is the ECS apart of?
The endogenous antinociceptive system.
What does CBR stand for?
Cannabinoid Receptor
Where are these CBRs located?
Peripheral, spinal, and supraspinal neurons.
What do the CBRs do in these specific neurons?
Supress nociceptive transmission
Where are CBRs present?
Immune cells and regulate inflammatory responses.
What are the CBR ligands an alternative for?
Opiods
Is there risk with the administration of drugs targeting the ECS? What cannabinoid receptor in particular?
Yes, it comes with the risk of cognitive adverse effects/ disruption of the ECS regulation of reward system.
In particular, it is the issue with the CB1 receptor
What prevents seizures?
Convential anti-epileptic drugs
What does these anti-elipetic drugs do in particular?
Block sodium or calcium channels, OR enhance GABA function to reduce the release of excitatory glutamte.
What does GABA stand for?
Gamma-aminobutyric acid
What are the major side-effects of anti-eplieptic drugs?
-Impairment of motor function
-Cognitive dysfunction
-Emotional lability
What specific cannabinoids have evidence of potentially reducing seizures?
THC and other CB1 agonists
When and who was the main source of discovering the cannabinoids that could help with seizures?
Chesher, Jackson, and Starmer in 1974
In 1973, (a) how did they administer the test to observe how THC effected seizures? (b) What animals did they test on? (c) Who wrote this paper?
(a) Orally (160-200 mg/kg doses)
(b) Mice
(c) Boggan, Steele, and Freedman
What other CB1 agonist decreased the seizure severity in rodent models?
WIN55,212
What does CB1 act synergistically with? And acts as a co-administor with what? What did this do as a result?
The 5-HT2B receptor and acts as a co-administor of WIN55,212 and 5-HT2B agonist RO60-0175. As a result it decreased seizures.
What inhibition results in anti-seizure activity?
Monoacylglycerol, with 2-AG activating CB1
What happens in FAAH inhibition?
Leads to increase in intracellular AEA levels and leads to pro-seizure activitiy
What was the greatest succces in treating seizures?
CBD
Does RO60-0175 have any effect on seizure patients on its own?
No.
Increase of what two endocannabinoids would potentially be seen as an anti-seizure treatment?
AEA and A2-G
Inhibition of what metabolic enzyme causes more seizure activity?
FAAH inhibition
Inhibition of what endocannabinoid causes a decrease in seizure activity?
Anadamide
What is an oral solution containing CBD?
Epidiolex
What is the two forms of epliepsy?
-Lennox-Gastaut syndrome
-Dravet syndrome
What is negative allosteric modulation?
A substance that, by binding to a receptor at site other than the primary site, instead reduces the activity of the ligand that normally binds to the site.
What is rimonabant known for?
Anti-obesity agent. A potent CB1 inverse agonist.
What did rimonabant cause? Was it withdrawn from the market?
Depression and anxiety. Yes it was withdrawn from the market due to those reasons.
What can targeting the ECS do?
Could be a potential strategy to design novel psychotic drugs, including anxiolytics.
What would be a natural CB1 agonist?
THC
What was supposed to be a promising direction to develop a new class of anxiolytic drugs?
CB1 Agonists
What is one of the the methods in order to reduce anxiety in patients?
Inhibit eCB degrading enzymes in order to indirectly activate CB1 by 2-AG or AEA
What did FAAH overexpression in hippocampal nuerons show?
Decreased levels in AEA in the hippocampus and resulted in anxiety-like behavior.
How did they study the ability to reduce anxiety in rodents?
Scientists gave rodents NMDA in order to induce anxiety like behavior, then introduced the URB602 (an MAGL inhibitor) in order to to block MAGL and increase the 2-AG in the blood stream in order to reduce anxiety like behavior.
What is NMDA?
N-methyl-D aspratate
What is the strategy that includes the ECS in order to target depressive disorders?
Direct or indirect CB1 activation
What is a CB1 and CB2 agonist that prevented anhedonia in a rodent model? What is the concentration?
WIN55,212-2 (0.5 mg/kg)
What is anhendonia?
Inability to feel pleasure
What is targeted in depressive disorders?
eCB degrading enzymes
In a rodent model what prevented anhedonia? What was the concentration?
FAAH inhibitor, URB597. 0.3 mg/kg
What is indirect activation?
By inhibiting degrading enzymes
Which strain of cannabis is known for a mild potential for addiction?
C. Sativa
What is a way to potentially omit the problem of addiction?
CB1neutral antagonists
What was tested in rodent models of opiod addiction? What did it also decrease in mice?
AM4113. It also decreased alcohol consumption.
What can be helpful for withdrawal symptoms?
CB1 agonists
What also increase eCB levels?
Physical exercise, this can also be part of the treatment of withdrawl syndromes
What is the second most prominent target in ECS for fighting the addiction?
CB2
What increased ethanol intake?
CB2 antagonist (AM630)
What decrease ethanol intake?
CB2 agonist (JWH133)
Where can CB2 also be found?
The brain
What happens when combining CB1 antagonism with CB2 agonism?
May be a reasonable strategy for fighting addiction because of recent finding that opposing action on these two receptors has a synergistic effect on reward processing?
What activation impairs memory?
CB1 activation
What enhances memory?
CB1 antagonists
What are symptons of tramatic brain injury (TBI)?
Impaired spacial learning and memory
What is the impaired spacial learning and memory connected to?
Increased 2-AG levels
What did the administartion of CB1 antagonist AM281 in mice do?
Ameliorates symptons of impaired spacial learning and memory
What did low dosages of Delta-9-THC show?
Improved cognitive performance of old mice in which CB1 was crucial
What is hormesis?
A substance that is typically a problem at higher doses, can be useful at lower doses?
What is neurodegeneration?
Neuron deteration in brain/CNS
What is neurogenesis?
The generation of new neurons
What takes in part in the regulation of neurogenesis?
CB1, CB2, GPR55
What is crucial for proligeration and differentiation of neural stem cells?
CB1 and GPR55
Why may endocannabinoid signaling be beneficial?
Impact on attenuating neurotoxicity and neuroinflammation
What worsens symptoms in Alzheimer’s disease?
CB1 deletion
What did the CB1 agonist ACEA exhibit?
Anti-apoptotic action on neurons and reduced and cognitive impairment in the Alzheimer’s disease rodent model?
What is anti-apoptotic?
Anti cell death
What does the activation of CB2 do?
Leads to anti-inflammatory action
Do cannabinoids increase or decrease appetite?
Increase appetite
How is the increase of appetite mediated?
By CB1 activation in the forebrain neurons, hypothalmus and in a mesolimbic dopamine system
What does ECS deregulation contribute to?
Type 2 Diabetes Mellitus
What was shown to reverse diabetic neuropath? Via what?
CB1 antagonists (JD5037) via the modulation of glucose transport 2 expression and activity in renal proximal tubule cells.
What occurs in diabetes?
CB1 receptors are upregulated in the kidney contributing to: renal inflammation, oxidative stress, tubular dysfunction, and glucose reabsorption abnormalitites
What does JD5037 not cross? Why is this important? What does this mean about its location?
It does not cross the blood-brain barrier. Avoids sides effects such as depression or anxiety that had been seen in examples like rimonabant. This means its localized peripherally.
What can happen to the cardiovascular system?
Has adverse effect which includes ischemic stroke.
What does the modulation of the ECS result in?
Alleviation of hypertension, atheroscierosis, mycardial ischemia, and related diseases
What did CB1 and CB2 agonists show related to cancer?
Shown to elicit antitumor properties both in vitro and in vivo.
What is something to look at for a cause of cancers?
ECS ovexpression in tumor cells
What has shown a positive result in triple negative breast cancer studies? What was the result?
A combination with photodynamic therapy with CB2 agonist (JWH-133). This resulted in synergistic inhibition of tumor growth and extended survival time in mice.
