Tag Archives: neuroprotective

Endocannabinoid 2-arachidonylglycerol protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through CB1 receptor.

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“Homocysteine (Hcy) is a high risk factor for Alzheimer’s disease (AD). Caudate nucleus (CN), the major component of basal ganglia in the brain, is also involved in many neurological disorders.

2-Arachidonoylglycerol (2-AG), the true natural ligand for cannabinoid type-1 (CB1) receptors and the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in the hippocampus and CN.

In the present work, we explored that 2-AG significantly protects CN neurons in culture against Hcy-induced response.

2-AG is capable of inhibiting elevation of Hcy-induced cyclooxygenase-2 expression associated with nuclear factor-kappaB/p38MAPK/ERK1/2 signaling pathway through CB1 receptors-dependent way in primary cultured CN neurons.

Our study reveals the therapeutic potential for 2-AG for the treatment of neurodegenerative diseases, such as AD.”

http://www.ncbi.nlm.nih.gov/pubmed/25007951

Effect of Homocysteine on Voltage-Gated Sodium Channel Currents in Primary Cultured Rat Caudate Nucleus Neurons and Its Modulation by 2-Arachidonylglycerol.

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“Homocysteine (Hcy) is an important risk factor for Alzheimer’s disease (AD) and other neurodegenerative diseases. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders.

2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects from many stimuli in the central nervous system (CNS).

Furthermore, it has been reported that voltage-gated sodium channels (VGSCs) are the common targets of many neuronal damages and drugs.

However, it is still not clear whether VGSCs are involved in the neurotoxicity of Hcy and the neuroprotective effect of 2-AG in CN neurons. In the present study, whole-cell patch clamp recording was used to invest the action of Hcy on sodium currents in primary cultured rat CN neurons and its modulation by 2-AG.

The results showed that in cultured CN neurons, pathological concentration of Hcy (100 μM) significantly increased the voltage-gated sodium currents (I Na) and produced a hyperpolarizing shift in the activation-voltage curve of I Na.

The further data demonstrated 2-AG is capable of suppressing elevation of Hcy-induced increase in I Na and hyperpolarizing shift of activation curves most partly through CB1 receptor-dependent way.

Our study provides a better understanding of Hcy-associated neurological disorders and suggests the therapeutic potential for 2-AG for the treatment of these diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26179279

Cannabinoid and nitric oxide signalling interplay in the modulation of hippocampal hyperexcitability: study on electrophysiological and behavioural models of temporal lobe epilepsy in the rat.

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“A growing bulk of evidence suggests that cannabinoid system plays a pivotal role in the control of hyperexcitability phenomena.

Notwithstanding, the anticonvulsant action of cannabinoids has not been fully addressed, in particular the involvement of potential cellular neuromodulators, for instance nitric oxide.

In the current study, we focused on two distinct rat models of temporal lobe epilepsy, the Maximal Dentate Activation and the Pilocarpine-induced acute seizures, providing both electrophysiological and behavioural data on cannabinoid and nitrergic system interplay.

MDA study showed that these drugs protected animals in a dose-dependent manner from electrically-induced epileptiform discharges.

In the light of this, our findings suggest a putative antagonism between CBr-activated pathway and NO signalling in the context of neuronal hyperexcitability and contribute to elucidate possible synaptic processes underlying neuroprotective properties of cannabinoids, with a view to better integrate antiepileptic therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/26135674

CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.

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“The global pandemic of HIV infection currently afflicts 34 million individuals, has killed over 25 million people since 1981, and is the cause of death in an estimated 1.8 million people per year.

Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients…

Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes.

Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model…

These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia.

Overall, this study confirms that gp120 is capable of damaging human dopaminergic neurons, that this damage involves human microglia, and that synthetic cannabinoids can alleviate this damage through mechanisms involving human microglia.

Thus, the results of these experiments set the stage for further studies designed to tease out the role human microglia have in the mechanisms underlying the toxic effects of HIV-1 on human dopaminergic neurons and understanding the microglial-centered mechanisms underlying the protective effects of selected synthetic cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798286/

Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage.

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“In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC)… protects the brain from different insults that cause cognitive deficits.

Because various insults may trigger a neuroinflammatory response that leads to secondary damage to the brain, the current study tested whether this extremely low dose of THC could protect the brain from inflammation-induced cognitive deficits…

Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation-induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/25042014

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

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“Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family.

Both CB1 and CB2 mRNA and proteins are present in the heart.

THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro.

We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults.

The present study was aimed to test and characterize the cardioprotective effects of a very low dose of THC…

All protocols of THC administration were found to be beneficial.

CONCLUSION:

A single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage.”

http://www.ncbi.nlm.nih.gov/pubmed/23537701

Combined neuroprotective action of adenosine A1 and cannabinoid CB1 receptors against NMDA-induced excitotoxicity in the hippocampus.

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“Both adenosine A1 and cannabinoid CB1 receptors trigger similar transduction pathways and protect against neurotoxic insults at the hippocampus, but their combined neuroprotective potential has not been investigated.

We set forth to assess the combined action of A1 and CB1 receptors against glutamate NMDA receptor-mediated excitotoxicity at the hippocampus…

The results suggest that both CB1 and A1 receptors produce additive cumulative neuroprotection against NMDA-induced excitotoxicity in the hippocampus.”

http://www.ncbi.nlm.nih.gov/pubmed/26065937

New horizons for newborn brain protection: enhancing endogenous neuroprotection.

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“Intrapartum-related events are the third leading cause of childhood mortality worldwide and result in one million neurodisabled survivors each year. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE).

The contribution of pure hypoxia-ischaemia (HI) to NE has been debated; over the last decade, the sensitising effect of inflammation in the aetiology of NE and neurodisability is recognised.

Therapeutic hypothermia is standard care for NE in high-income countries; however, its benefit in encephalopathic babies with sepsis or in those born following chorioamnionitis is unclear.

It is now recognised that the phases of brain injury extend into a tertiary phase, which lasts for weeks to years after the initial insult and opens up new possibilities for therapy.

There has been a recent focus on understanding endogenous neuroprotection and how to boost it or to supplement its effectors therapeutically once damage to the brain has occurred as in NE.

In this review, we focus on strategies that can augment the body’s own endogenous neuroprotection.

We discuss in particular remote ischaemic postconditioning whereby endogenous brain tolerance can be activated through hypoxia/reperfusion stimuli started immediately after the index hypoxic-ischaemic insult.

Therapeutic hypothermia, melatonin, erythropoietin and cannabinoids are examples of ways we can supplement the endogenous response to HI to obtain its full neuroprotective potential.

Achieving the correct balance of interventions at the correct time in relation to the nature and stage of injury will be a significant challenge in the next decade.”

http://www.ncbi.nlm.nih.gov/pubmed/26063194

Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

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“Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited.

Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication…

In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.”

http://www.ncbi.nlm.nih.gov/pubmed/25933444

Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine.

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“Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate.

Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity.

URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury.

Using confocal liver intravital microscopy, we observed that CBD reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure.

Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics.

These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.”

http://www.ncbi.nlm.nih.gov/pubmed/25999668

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427116/