Repeated treatment with delta 9 -THC and other CB1 receptor agonists result in the development of tolerance to its most acute behavioral and pharmacological effects [47,48,49,50]. Delta 9 -THC has been shown to lead to tolerance of hypoactivity, hypothermia, anti-nociception, catalepsy and pentobarbital-induced sleep prolongation [51,52,53]. In fact, 14 day-repeated treatment with delta 9 -THC (10 mg/kg) led to tolerance of the hypothermic and also neuroprotective effects. Additionally, the expression levels of CB1 receptor were down-regulated in mice with repeated doses of 10 mg/kg . On the other hand, repeated treatment with CBD did not lead to development of tolerance in the cerebroprotective effect on infarction. CBD induced an increase in cerebral blood flow (CBF) even after 14 days of repeated treatment. Since these effects of CBD were in part inhibited by WAY100135, CBD may not be full 5-HT1A agonist. It is known that, 8-OH-DPAT, a complete 5HT1A agonist, induces tolerance , while a 5-HT1A receptor partial agonist such as buspirone does not . For that reason, the neuroprotective effect of CBD may be mediated through partial agonistic effect on the 5-HT1A receptor.
Dexanabinol (HU-211) is a synthetic, nonpsychotropic cannabinoid . It has been shown to act as a noncompetitive N-methyl-D-aspartate receptor antagonist , as well as having antioxidant , anti-inflammatory effects [93,94]. The therapeutic time window of nonpsychotropic cannabinoid, HU-211 in closed head injury was first reported by Mechoulam’s research group in 1993 . HU-211 dissolved in middle-chain triglycerides (MCT) oil at a dose of 25 mg/kg was given intraperitoneally immediately and 1, 2, or 3 h after impact. The drug was found to be very effective in improving motor function recovery when given 2 h after the injury. In addition, Shohami and co-workers have shown the long-term effect of HU-211 on motor and memory functions after closed head injury in the rat . HU-211 (5 mg/kg) was administered intravenously at 4 or 6 h after closed head injury. Cognitive functions were evaluated using the Morris water maze, with rats trained either before or after closed head injury. The data showed that HU-211 was a potent cerebroprotective agent, with a therapeutic window of about 4 h. Moreover, this compound HU-211 was also used for cerebral ischemia. Belayev and co-workers have reported that HU-211 (4 mg/kg, i.v.) significantly improved neurological deficits and reduced brain damage 60 min after forebrain ischemia in rats, but neuroprotection was no longer significant after 3 h . Leker’s research group demonstrated that treatment with HU-211, dexanabinol (4.5 mg/kg) 1 h and 3 h but not 6 h after permanent middle cerebral artery occlusion in rats improved motor function and reduced infarct volume 24 h post ischemia .
2.4. Cerebroprotective Effect without the Development of Tolerance
Therapeutic time window of CBD and delta 9 -THC in pre-clinical study.
We have previously reported that CBD (3 mg/kg) has a potent and long-lasting neuroprotective effect when administered both pre- and post-ischemia, whereas only pre-ischemic treatment with delta 9 -THC (10 mg/kg) reduced the infarction size when administered 24 hours after 4 h MCAo in mice. The neuroprotective effect of delta 9 -THC and other cannabinoids is related to the CB1 receptor-mediated inhibition of voltage-sensitive Ca 2+ channels, which reduces Ca 2+ influx, glutamate release, and excitotoxicity . In fact, delta 9 -THC inhibited the massive release of glutamate, but this neuroprotective effect of delta- 9 THC was inhibited by the CB1 receptor antagonist SR141716 , which suggest that delta 9 -THC is neuroprotective as a pre-ischemic treatment via inhibition of glutamate excitotoxicity. Actually, treatment with delta 9 -THC immediately after reperfusion did not prevent cerebral infarction. On the other hand, CBD was neuroprotective even when administered 6 hours after cerebral ischemia (2 hours after reperfusion). In addition, CBD significantly inhibited the myeloperoxidase activity of neutrophils at 1 hour and 20 hours after reperfusion and suppressed the decrease in CBF due to the failure of cerebral microcirculation after reperfusion. In addition, CBD decreased the number of Iba1- and GFAP-positive cells and improved neurological score and motor coordination at 3 days after cerebral ischemia. We concluded that the therapeutic time window of CBD was 6 hours after onset of ischemia in early treatment. CBD had a potent and long-lasting neuro- protective effect and prevented progressive post-ischemic injury . In a more recent study, we reported that repeated treatment with CBD from 1 day or 3 days after cerebral ischemia improved the functional deficits, such as neurological score and motor coordination, and survival rates. In addition, both groups did not increase the HMGB1 level in plasma, and decreased the number of Iba1 expressing HMGB1 positive cells and TUNEL positive cells, which suggest that CBD may be cerebroprotective not only during the early phase, but also during the chronic phase after ischemic stroke . However, treatment with CBD from Day 5 did not improve the functional outcome Day 14 after cerebral ischemia. As described above, CBD has a potent anti-inflammatory effect, such as inhibition of glial activation. Activated microglia and reactive astrocytes have also a role of beneficial in ischemic brain. For example, microglia can produce neurotorophic factors such as brain-derived neurotorophic factor, insulin-like growth factor 1 . And, reactive astrocytes can also release many growth factors such as nerve growth factor . Taken together, a treatment with CBD in ischemic early phase may implicate the neuroprotective action through inhibition of acute inflammatory reaction, whereas ischemic delayed treatment with CBD may interfere with beneficial endogenous mechanisms.
3.3. A Synthetic Non-Competitive NMDA Antagonist, HU-211, Dexanabinol
Cannabinoids may play a role in neuroprotection in disorders such as stroke, Parkinson’s disease, traumatic brain injury and epilepsy. These disorders may be caused by the generation of free radicals, reactive oxygen species, and pro-inflammatory cytokines. Emerging data suggest that natural- and synthetic-cannabinoids show a potent anti-oxidant activity and anti-inflammatory reaction in in vivo and in vitro studies. Among cannabis compounds, CBD may represent a very promising agent with the highest prospect for therapeutic use. An Israeli pharmaceutical company called Pharmos was conducting human clinical trials using a synthetic dextrocannabinid, dexanabinol, which has neuroprotective properties through inhibition of NMDA glutamate receptors, as well as anti-inflammatory and antioxidant activities like CBD, in patients with severe traumatic brain injury  and had been granted orphan drug status by the FDA . However, in December 2004, Pharmos announced that no efficacy was observed as measured by the primary clinical outcome endopoint in Phase III TBI trials. After this announcement, SAPHIR and Pharmos investigators noted that there was a potential for selection bias that may creep into well-designed randomized clinical trials as a result of factors outside the control of investigators . In 2003, a clinical trial investigating the protective properties of CBD in neurodegeneration was also performed by GW pharmaceuticals, with the results still pending.
Within about two or three minutes, the neurons suffocate and die. This cell death is permanent; neurons do not grow back.
There are two markers scientists use to determine neuron health:
CBD is especially useful for neuron health.
What Is A Stroke?
All of our cells need oxygen and a source of energy to survive.
It’s also useful for reducing the chances of having another stroke in the future and protects against a lot of the damage that occurs during a stroke event. However, it’s important to talk to your doctor first, since CBD can interact with some medications.
Symptoms During The Stroke:
As soon as blood flow is cut off from a cell, it becomes sick.
Since ischemic strokes are caused by poor blood flow, it makes perfect sense to improve blood flow to the brain to prevent further damage.