“Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300 Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. Our results demonstrate the protective potential of the eCB system during excitotoxic influences.” https://www.ncbi.nlm.nih.gov/pubmed/28192082]]>
Tag Archives: neuroprotection
Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease.
“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.” https://www.ncbi.nlm.nih.gov/pubmed/28189739]]>
Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease.
“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases.
Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement.
Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising.
In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways.
Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.”
Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.
“Sulfur dioxide (SO2) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation. Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction. Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS). In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors. Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO2 inhalation.” https://www.ncbi.nlm.nih.gov/pubmed/28115138]]>
Alteration of the endocannabinoid system in mouse brain during prion disease.
“Prion diseases are neurodegenerative disorders characterized by deposition of the pathological prion protein (PrPsc) within the brain of affected humans and animals. Microglial cell activation is a common feature of prion diseases; alterations of various neurotransmitter systems and neurotransmission have been also reported. Owing to its ability to modulate both neuroimmune responses and neurotransmission, it was of interest to study the brain endocannabinoid system in a prion-infected mouse model. The production of the endocannabinoid, 2-arachidonoyglycerol (2-AG), was enhanced 10 weeks post-infection, without alteration of the other endocannabinoid, anandamide. The CB2 receptor expression was up-regulated in brains of prion-infected mice as early as 10 weeks and up to 32 weeks post-infection whereas the mRNAs of other cannabinoid receptors (CBRs) remain unchanged. The observed alterations of the endocannabinoid system were specific for prion infection since no significant changes were observed in the brain of prion-resistant mice, that is, mice devoid of the Prnp gene. Our study highlights important alterations of the endocannabinoid system during early stages of the disease long before the clinical signs of the disease.” https://www.ncbi.nlm.nih.gov/pubmed/21195746
“Prion diseases are a group of neurodegenerative diseases caused by prions, which are “proteinaceous infectious particles.” Prion diseases are caused by misfolded forms of the prion protein, also known as PrP. These diseases affect a lot of different mammals in addition to humans. The human forms of prion disease are most often the names Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gertsmann-Straussler-Scheinker syndrome (GSS), kuru and variably protease-sensitive prionopathy (VPSPr). All of these diseases are caused by just slightly different versions of the same protein, so we refer to them all as prion diseases.” http://www.prionalliance.org/2013/12/02/what-are-human-prion-diseases/
“Eating meat contaminated with bovine spongiform encephalopathy and its hallmark misshapen proteins, called prions, can cause a fatal and untreatable brain disorder,” http://www.sciencemag.org/news/2016/12/mad-cow-disease-remains-threat-new-blood-tests-could-detect-it
“Prions are terrifying.”
“Marijuana Kills MRSA and Inhibits Prions That Cause Neurodegenerative Disease; Still Recognized by Feds As a Dangerous Drug.” http://www.medicaldaily.com/marijuana-kills-mrsa-and-inhibits-prions-cause-neurodegenerative-disease-still-recognized-feds
“Fact: Cannabis Kills MRSA, Disrupts Prion Diseases” http://www.eastbayexpress.com/LegalizationNation/archives/2013/07/29/fact-cannabis-kills-mrsa-disrupts-prion-diseases
“Antibacterial cannabinoids from Cannabis sativa: a structure-activity study.” http://www.ncbi.nlm.nih.gov/pubmed/18681481
“Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons against Prion Toxicity. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug. ” http://www.jneurosci.org/content/27/36/9537.full
Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis.
“Targeting the CB2 receptor afforded neuroprotection in SOD1G93A mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1G93A mutant mice. Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1). In summary, our results demonstrated a marked up-regulation of CB2 receptors occurring in the spinal cord in canine DM, which was concentrated in activated astrocytes. Such receptors may be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.” https://www.ncbi.nlm.nih.gov/pubmed/28069688]]>
Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection.
“Recent evidence shows that the endocannabinoid system is involved in the pathogenesis of numerous neurodegenerative diseases of the central nervous system. Pharmacologic modulation of cannabinoid receptors or the enzymes involved in the synthesis, transport, or breakdown of endogenous cannabinoids has proved to be a valid alternative to conventional treatment of these diseases.
In this review, we will examine recent findings that demonstrate the involvement of the endocannabinoid system in glaucoma, a major neurodegenerative disease of the eye that is a frequent cause of blindness.
Experimental findings indicate that the endocannabinoid system contributes to the control of intraocular pressure (IOP), by modulating both production and drainage of aqueous humor.
There is also a growing body of evidence of the involvement of this system in mechanisms leading to the death of retinal ganglion cells, which is the end result of glaucoma.
Molecules capable of interfering with the ocular endocannabinoid system could offer valid alternatives to the treatment of this disease, based not only on the reduction of IOP but also on neuroprotection.”
https://www.ncbi.nlm.nih.gov/pubmed/18929127
[Possibilities of applying cannabinoids' in the treatment of glaucoma].
“Over a period of several decades numerous scientific research has proven that, regardless of the route of administration, cannabinoids are able to decrease intraocular pressure. What is more, these compounds are characterized by neuroprotection and vasodilatation properties, that additionally substantiate it’s therapeutic utility in conservative treatment of glaucoma. So far, it has not been described in details what mechanism is used to lower the intraocular pressure by cannabinoids. Nevertheless, the presence of endocannabinoid receptors in structures of the eye responsible for formation and outflow of aqueous humor is an explanation for effectiveness of these compounds, when administered in topical form. These days, with the aid of modern pharmacological technology are available significantly bigger possibilities of improving bioavailability of cannabinoids administered to the eye than in the past, as well as limitation of it’s undesired side effects.” https://www.ncbi.nlm.nih.gov/pubmed/19112869]]>
[Possibilities of applying cannabinoids’ in the treatment of glaucoma].
“Over a period of several decades numerous scientific research has proven that, regardless of the route of administration, cannabinoids are able to decrease intraocular pressure.
What is more, these compounds are characterized by neuroprotection and vasodilatation properties, that additionally substantiate it’s therapeutic utility in conservative treatment of glaucoma.
So far, it has not been described in details what mechanism is used to lower the intraocular pressure by cannabinoids. Nevertheless, the presence of endocannabinoid receptors in structures of the eye responsible for formation and outflow of aqueous humor is an explanation for effectiveness of these compounds, when administered in topical form.
These days, with the aid of modern pharmacological technology are available significantly bigger possibilities of improving bioavailability of cannabinoids administered to the eye than in the past, as well as limitation of it’s undesired side effects.”
The arguments for and against cannabinoids application in glaucomatous retinopathy.
“Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder.
Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma.
Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye.
In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature.
In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed.”