The endocannabinoid system in neurodegeneration

Endocannabinoids are bioactive lipids, that comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied endocannabinoids, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol, the psychoactive principle of hashish and marijuana. It is known that the activity of endocannabinoids at their receptors is limited by cellular uptake through specific membrane transporters, followed by intracellular degradation by a fatty acid amide hydrolase (for AEA and partly 2-AG) or by a monoacylglycerol lipase (for 2-AG). Together with AEA, 2-AG and congeners, the proteins that bind, transport and metabolize these lipids form the "endocannabinoid system". This new system will be briefly presented in this review, in order to put in a better perspective the role of the endocannabinoid pathway in neurodegenerative disorders, like Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of endocannabinoid receptors, or of inhibitors of endocannabinoid metabolism, as next-generation therapeutics will be discussed.     

Immunotherapy as a therapeutic treatment for neurodegenerative disorders

Human neurodegenerative illnesses such as Alzheimer's disease and Creutzfeldt-Jakob disease exact an enormous cost on individuals, families and society. For these and related disorders, current treatment is largely symptomatic without influencing the underlying disease process. Until recently, the development of immunotherapeutic approaches to neurodegenerative disorders had been almost completely ignored despite growing successes against other non-infectious diseases such as cancer. However, since Schenk and colleagues described the antibody-mediated clearance of amyloid plaques in a transgenic mouse model of Alzheimer's disease, a number of studies have confirmed the feasibility of this strategy for several neurodegenerative disorders including Huntington's disease and prion diseases. These reports offer the exciting prospect that either the immune system or its derivative components can be harnessed to fight the misfolded and/or aggregated proteins that accumulate in many neurodegenerative illnesses. If the remarkable power of clonal expansion, specificity and efficiency of the immune system can successfully inactivate these abnormal proteins, real hope exists that effective immunotherapeutic treatments for neurodegenerative illnesses may be available in the near future.     

Adipocytes: Potential link between endocannabinoid system and atherosclerosis

Obesity is an increasing problem, with a growing number of people worldwide classed as overweight and at high risk for developing other serious conditions, such as coronary heart disease and diabetes. The expansion of the size and number of adipocytes is the key characteristic of obesity. Rimonabant, a novel anti-obesity drug, not only exhibits its central effects such as reducing food intake but also influences lipid metabolism in adipocytes through blocking endocannabinoid system. The endocannabinoid system has multiple biological effects, and it has become new target of cardiometabolic risk control. Recently, the connection of adiopocytes and atherosclerosis has been extensively explored. It is believed that adipocytes play critical roles in the development of atherosclerosis. Adipocyte is itself recognized as an important site of production of inflammation-related proteins (adipokines), which is influenced by energy and lipid metabolism in adipocytes. The endocannabinoid system may regulate lipogenesis and adipokines' production in adipocytes. We hypothesize that adipocytes will be a link between endocannabinoid system and atherosclerosis. Exploring the effect and mechanism of endocannabinoid system on adipocyte is thus likely to be very helpful for further understanding the critical role that adipocytes plays in the development and progress of obesity and atherosclerosis, and may provide potential therapeutic options for obesity and atherosclerosis.     

Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disorder which accounts for 60–70% of the 50 million worldwide cases of dementia and is characterised by cognitive impairments, many of which have long been associated with dysfunction of the cholinergic system. Although the M₁ muscarinic acetylcholine receptor (mAChR) is considered a promising drug target for AD, ligands targeting this receptor have so far been unsuccessful in clinical trials. As modulatory receptors to cholinergic transmission, the endocannabinoid system may be a promising drug target to allow fine tuning of the cholinergic system. Furthermore, disease-related changes have been found in the endocannabinoid system during AD progression and indeed targeting the endocannabinoid system at specific disease stages alleviates cognitive symptoms in numerous mouse models of AD. Here we review the role of the endocannabinoid system in AD, and its crosstalk with mAChRs as a potential drug target for cholinergic dysfunction.     

The endocannabinoid system: Its roles in energy balance and potential as a target for obesity treatment

Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.     

The endocannabinoid system: a revolving plate in neuro-immune interaction in health and disease

Studies of the last 40 years have brought to light an important physiological network, the endocannabinoid system. Endogenous and exogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors. This modulatory homoeostatic system operates in the regulation of brain function and also in the periphery. The cannabinoid system has been shown to be involved in regulating the immune system. Studies examining the effect of cannabinoid-based drugs on immunity have shown that many cellular and cytokine mechanisms are modulated by these agents, thus raising the hypothesis that these compounds may be of value in the management of chronic inflammatory diseases. The special properties of endocannabinoids as neurotransmitters, their pleiotropic effects and the impact on immune function show that the endocannabinoid system represents a revolving plate of neural and immune interactions. In this paper, we outline current information on immune effects of cannabinoids in health and disease.     

The Endocannabinoid System and Extinction Learning

The endocannabinoid system has emerged as a versatile neuromodulatory system, implicated in a plethora of physiological and pathophysiological processes. Cannabinoid receptor type 1 (CB1 receptor) and endocannabinoids are widely distributed in the brain. Their roles in learning and memory have been well documented, using rodents in various memory tests. Depending on the test, the endocannabinoid system is required in the acquisition and/or extinction of memory. In particular, the activation of CB1 receptor-mediated signaling is centrally involved in the facilitation of behavioral adaptation after the acquisition of aversive memories. As several human psychiatric disorders, such as phobia, generalized anxiety disorders, and posttraumatic stress disorder (PTSD) appear to involve aberrant memory processing and impaired adaptation to changed environmental conditions, the hope has been fuelled that the endocannabinoid system might be a valuable therapeutic target for the treatment of these disorders. This review summarizes the current data on the role of the endocannabinoid system in the modulation of extinction learning.     

Clinical psychoacoustics in Alzheimer's disease central auditory processing disorders and speech deterioration

BACKGROUND: Difficulty in speech understanding in the presence of background noise or competing auditory signals is typically present in central auditory processing disorders. These disorders may be diagnosed in Alzheimer's disease as a result of degeneration in the central auditory system. In addition perception and processing of speech may be affected. MATERIAL AND METHODS: A MEDLINE research was conducted in order to answer the question whether there is a central auditory processing disorder involved in Alzheimer's disease. A second question to be investigated was what, if any is the connection, between central auditory processing disorders and speech deterioration?Articles were retrieved from the Medline to find relevance of Alzheimer's dis ease with central auditory processing disorders, they summed up to 34. Twelve papers were studied that contained testing for CAPD through psychoacoustic investigation. An additional search using the keywords 'speech production' and 'AD' produced a result of 33 articles, of them 14 are thoroughly discussed in this review as they have references concerning CAPD. The rest do not contain any relavent information on the central auditory system. RESULTS: Psychoacoustic tests reveal significantly lower scores in patients with Alzheimer's disease compared with normal subjects. Tests concerning sound localization and perception of tones as well as phoneme discrimination and tonal memory reveal deficits in Alzheimer's disease. Central auditory processing disorders may exist several years before the onset of clinical diagnosis of Alzheimer's disease. Segmental characteristics of speech are normal. Deficits exist concerning the supra-segmental components of speech. CONCLUSIONS: Central auditory processing disorders have been found in many cases when patients with Alzheimer's disease are tested. They may present as an early manifestation of Alzheimer's disease, preceding the disease by a minimum of 5 and a maximum of 10 years. During these years changes in the central auditory system, starting in the temporal lobe, may produce deficits in speech processing and production as hearing and speech are highly connected human functions. Another theory may be that spread of degeneration of the central nervous system has as a consequence, speech deterioration. Further research and central auditory processing disorders testing in the elderly population are needed to validate one theory over the other.     

Acute neuronal injury,excitotoxicity, and the endocannabinoid system

The endocannabinoid system is a valuable target for drug discovery, because it is involved in the regulation of many cellular and physiological functions. The endocannabinoid system constitutes the endogenous lipids anandamide, 2-arachidonoylglycerol and noladin ether, and the cannabinoid CB₁ and CB₂ receptors as well as the proteins for their inactivation. It is thought that (endo)cannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. This paper reviews recent developments in the endocannabinoid system and its involvement in neuroprotection. Exogenous (endo)cannabinoids have been shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by CB₁-mediated inhibition of glutamatergic transmission, reduction of calcium influx, and subsequent inhibition of deleterious cascades, TNF-α formation, and anti-oxidant activity. It has been suggested that the release of endogenous endocannabinoids during neuronal injury might be a protective response. However, several observations indicate that the role of the endocannabinoid system as a general endogenous protection system is questionable. The data are critically reviewed and possible explanations are given.     

The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease

The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.     

内源性大麻素系统与神经保护浅识

内源性大麻素系统包括大麻素受体、内源性配体以及参与其合成与降解的酶类,在人体内广泛分布,参与诸多生理和病理生理过程。新近报道内源性大麻素系统在中枢神经系统的许多疾病的病理生理过程中扮演重要的角色。对内源性大麻素系统的研究,不仅能阐明一些疾病的病理生理机制,还有助于新药研发并为疾病治疗提供新的方向。本文基于现有的文献报道,就内源性大麻素系统及其在一些中枢神经疾病特别是脑缺血和帕金森病的发病机制的新进展进行综述。     

Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism

Cannabinoid receptors and their endogenous ligands are potent inhibitors of neurotransmitter release in the brain. Here, we show that in a rat model of Parkinson's disease induced by unilateral nigral lesion with 6-hydroxydopamine (6-OHDA), the striatal levels of the endocannabinoid anandamide (AEA) were increased, while the activity of its membrane transporter and hydrolase (fatty-acid amide hydrolase, FAAH) were decreased. These changes were not observed in the cerebellum of the same animals. Moreover, the frequency and amplitude of glutamate-mediated spontaneous excitatory post-synaptic currents were augmented in striatal spiny neurones recorded from parkinsonian rats. Remarkably, the anomalies in the endocannabinoid system, as well as those in glutamatergic activity, were completely reversed by chronic treatment of parkinsonian rats with levodopa, and the pharmacological inhibition of FAAH restored a normal glutamatergic activity in 6-OHDA-lesioned animals. Thus, the increased striatal levels of AEA may reflect a compensatory mechanism trying to counteract the abnormal corticostriatal glutamatergic drive in parkinsonian rats. However, this mechanism seems to be unsuccessful, since spontaneous excitatory activity is still higher in these animals. Taken together, these data show that anomalies in the endocannabinoid system induced by experimental parkinsonism are restricted to the striatum and can be reversed by chronic levodopa treatment, and suggest that inhibition of FAAH might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinson's disease.     

Lipid rafts: A nexus for endocannabinoid signaling?

The endocannabinoids are endogenous agonists of the cannabinoid receptors and some members of the transient receptor potential, vanilloid type (TRPV), family of cation channels. Endocannabinoids along with their target receptors comprise a signaling system that is not well characterized. There have been many advances in our collective understanding of endocannabinoid signaling in the last decade and experimental evidence is mounting that pharmacological augmentation of endocannabinoid tone might have a significant therapeutic benefit in several disease states. However, the mechanisms responsible for the biosynthesis, cellular uptake, and intracellular processing of endocannabinoids are not well understood and have been the source of much debate. Recent studies have revealed a role for detergent insoluble membrane domains called lipid rafts in various aspects of signaling associated with the endocannabinoid anandamide. Intact detergent insoluble membrane domains appear to play a role in an anandamide-induced signaling cascade that is independent of G protein-coupled cannabinoid receptors or TRPV channels. Furthermore, detergent insoluble membrane domain-related endocytosis and recycling to lipid rafts appear to regulate the organization and localization of anandamide metabolites. We will discuss the implications that these findings have on the way we view endocannabinoid signaling, trafficking, and processing.     

Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states

The endogenous cannabinoid system has revealed potential avenues to treat many disease states. Medicinal indications of cannabinoid drugs including compounds that result in enhanced endocannabinoid responses (EER) have expanded markedly in recent years. The wide range of indications covers chemotherapy complications, tumor growth, addiction, pain, multiple sclerosis, glaucoma, inflammation, eating disorders, age-related neurodegenerative disorders, as well as epileptic seizures, traumatic brain injury, cerebral ischemia, and other excitotoxic insults. Indeed, a great effort has led to the discovery of agents that selectively activate the cannabinoid system or that enhance the endogenous pathways of cannabinergic signaling. The endocannabinoid system is comprised of three primary components: (i) cannabinoid receptors, (ii) endocannabinoid transport system, and (iii) hydrolysis enzymes that break down the endogenous ligands. Two known endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are lipid molecules that are greatly elevated in response to a variety of pathological events. This increase in endocannabinoid levels is suggested to be part of an on-demand compensatory response. Furthermore, activation of signaling pathways mediated by the endogenous cannabinoid system promotes repair and cell survival. Similar cell maintenance effects are elicited by EER through inhibitors of the endocannabinoid deactivation processes (i.e., internalization and hydrolysis). The therapeutic potential of the endocannabinoid system has yet to be fully determined, and the number of medical maladies that may be treated will likely continue to grow. This review will underline studies that demonstrate medicinal applications for agents that influence the endocannabinoid system.     

Endocannabinoid system in food intake and metabolic regulation

PURPOSE OF REVIEW: As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology. RECENT FINDINGS: The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood. SUMMARY: The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes.     

Selective reversible inhibition of human butyrylcholinesterase by aryl amide derivatives of phenothiazine

Evidence suggests that specific inhibition of butyrylcholinesterase may be an appropriate focus for the development of more effective drugs to treat dementias such as Alzheimer's disease. Butyrylcholinesterase is a co-regulator of cholinergic neurotransmission and its activity is increased in Alzheimer's disease, and is associated with all neuropathological lesions in this disease. Some selective butyrylcholinesterase inhibitors have already been reported to increase acetylcholine levels and to reduce the formation of abnormal amyloid found in Alzheimer's disease. Synthesized N-(10)-aryl and N-(10)-alkylaryl amides of phenothiazine are specific inhibitors of butyrylcholinesterase. In some cases, inhibition constants in the nanomolar range are achieved. Enzyme specificity and inhibitor potency of these molecules can be related to molecular volumes, steric and electronic factors. Computed logP values indicate high potential for these compounds to cross the blood-brain barrier. Use of such butyrylcholinesterase inhibitors could provide direct evidence for the importance of this enzyme in the normal nervous system and in Alzheimer's disease.     

Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function

The endocannabinoid system (ECS) is a construct based on the discovery of receptors that are modulated by the plant compound tetrahydrocannabinol and the subsequent identification of a family of nascent ligands, the ‘endocannabinoids’. The function of the ECS is thus defined by modulation of these receptors—in particular, by two of the best-described ligands (2-arachidonyl glycerol and anandamide), and by their metabolic pathways. Endocannabinoids are released by cell stress, and promote both cell survival and death according to concentration. The ECS appears to shift the immune system towards a type 2 response, while maintaining a positive energy balance and reducing anxiety. It may therefore be important in resolution of injury and inflammation. Data suggest that the ECS could potentially modulate mitochondrial function by several different pathways; this may help explain its actions in the central nervous system. Dose-related control of mitochondrial function could therefore provide an insight into its role in health and disease, and why it might have its own pathology, and possibly, new therapeutic directions.     

Physiological and pathological roles of interleukin-6 in the central nervous system

The cytokine interleukin-6 (IL-6) is an important mediator of inflammatory and immune responses in the periphery. IL-6 is produced in the periphery and acts systemically to induce growth and differentiation of cells in the immune and hematopoietic systems and to induce and coordinate the different elements of the acute-phase response. In addition to these peripheral actions, recent studies indicate that IL-6 is also produced within the central nervous system (CNS) and may play an important role in a variety of CNS functions such as cell-to-cell signaling, coordination of neuroimmune responses, protection of neurons from insult, as well as neuronal differentiation, growth, and survival. IL-6 may also contribute to the etiology of neuropathological disorders. Elevated levels of IL-6 in the CNS are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis. Moreover, several studies have shown that chronic overexpression of IL-6 in transgenic mice can lead to significant neuroanatomical and neurophysiological changes in the CNS similar to that commonly observed in various neurological diseases. Thus, it appears that IL-6 may play a role in both physiological and pathophysiological processes in the CNS.     

The role of NMDA receptors in the slow neuronal degeneration of Parkinson's disease

Summary Parkinson's disease is a disorder, in which neurons of various neuronal systems degenerate. Furthermore, in such degenerating neurons, the cytoskeleton seems to be affected. In this respect, Parkinson's disease resembles Alzheimer's disease. Since it has been shown, that elevated levels of intracellular calcium can disrupt the cytoskeleton and that the stimulation of glutamate (NMDA) receptors can cause high intracellular concentrations of calcium, it has been suggested, that the stimulation of glutamate receptors plays a role in the slow degeneration in Alzheimer's and Parkinson's disease. In case of the degeneration of the dopaminergic nigrostriatal system in Parkinson's disease, neurons that contain calcium binding protein appear to be less vulnerable than the neurons that lack it, suggesting that calcium binding protein might protect these neurons from degeneration by preventing that cytosolic calcium concentrations increase excessively. And, since there is in the nigrostriatal system a glutamatergic afferent pathway (the prefrontonigral projection) and since dopaminergic nigrostriatal neurons contain postsynaptic NMDA receptors, glutamatergic excitation may play a role in the degeneration of the nigrostriatal system in Parkinson's disease. If so, it may be possible to protect the neurodegeneration of these dopaminergic neurons by NMDA receptor antagonists.