CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 8, Issue 6, 2009

As I reflected about the progress in the endocannabinoid field for this Hot Topics issue, I cannot help but think of the recent losses to our community. In 2008, we were stunned by the untimely passing of two leaders in our field, Billy Martin (1943- 2008) and Mike Walker (1950-2008). I had the privilege of seeing both give lectures, and their research legacy is apparent from the tremendous impact they each had on endocannabinoid research. What is not as visible is the number of lives both Drs. Martin and Walker touched as mentors and “builders” of the next generation of scientists. As I think about Dr. Martin's contributions, the tetrad of cannabinoid effects comes to mind as a critical moment for our field. As the authors in this volume write about pain and CNS diseases in particular, I can see the links of those ideas to Dr. Martin's tetrad. From the tetrad of cannabinoid effects, particularly antinocipception, entire lab careers have sought to understand the role of cannabinoids in prevention of pain perception. In this edition, Drs. Guinnon and Hohmann's review of the pain literature focuses on two endocannabinoids, 2-arachidonyl glycerol and anandamide. Dr. Walker's lab also sought to understand the role of endocannabinoids in pain and his lab's website continues to proclaim that “pain kills.” It is fitting that the first review here also examines the role of endocannabinoids as potential therapies for pain perception. Critical to the understanding of the endocannabinoid involvement in pain perception and the linked-diseases is the ability of cannabinoids to change cellular responses. In the second paper, Drs. Dalton, Bass, Van Horn, and Howlett review the growing literature on endocannabinoid signal transduction pathways. From the receptors to the proteins to the nucleus, and back to the responses of the cell, these authors clearly lay out the molecular implications for endocannabinoids and their related compounds. This area is far from complete in terms of understanding, and our authors point out the newest research in the hepatocytes and adipose tissue, hinting at the relevance of endocannabinoids to appetite and obesity research.

The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB1 and CB2 receptor subtypes. Endocannabinoids, the brain's own cannabis-like substances, share the same molecular target as Δ9-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide and 2-arachidonoylglycerol, the two best characterized endocannabinoids identified to date, in controlling nociceptive responding. The roles of anandamide and 2-arachidonoylglycerol, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of endocannabinoid levels through inhibition of endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.

The endocannabinoids anandamide and 2-arachidonoylglycerol are lipid mediators that signal via CB1 and CB2 cannabinoid receptors and Gi/o-proteins to inhibit adenylyl cyclase and stimulate mitogen-activated protein kinase. In the brain, CB1 receptors interact with opioid receptors in close proximity, and these receptors may share G-proteins and effector systems. In the striatum, CB1 receptors function in coordination with D1 and D2 dopamine receptors, and combined stimulation of CB1-D2 receptor heteromeric complexes promotes a unique interaction to stimulate cAMP production. CB1 receptors also trigger growth factor receptor signaling cascades in cells by engaging in cross-talk or interreceptor signal transmission with the receptor tyrosine kinase (RTK) family. Mechanisms for CB1 receptor-RTK transactivation can include stimulation of signal transduction pathways regulated by second messengers as well as phospholipase C, metalloprotease cleavage of membrane-bound precursor proteins such as epidermal growth factor which activate RTKs, RTK autophosphorylation, and recruitment of non-receptor tyrosine kinases. CB1 and CB2 receptors are expressed in peripheral tissues including liver and adipose tissue, and are induced in pathological conditions. Novel signal transduction resulting from endocannabinoid regulation of AMP-regulated kinase and peroxisome proliferator-activated receptors have been discovered from studies of hepatocytes and adipocytes. It can be predicted that drug discovery of the future will be based upon these novel signal transduction mechanisms for endocannabinoid mediators.

Cannabinoid-based medicines have been proposed as clinically promising therapies in Parkinson's disease (PD), given the prominent modulatory function played by the cannabinoid signaling system in the basal ganglia. Supporting this pharmacological potential, the cannabinoid signaling system experiences a biphasic pattern of changes during the progression of PD. Thus, early and presymptomatic stages, characterized by neuronal malfunctioning but little evidence of neuronal death, are associated with desensitization/downregulation of CB1 receptors. It was proposed that these losses may be part of the pathogenesis itself, since they can aggravate different cytotoxic insults which are controlled in part by cannabinoid signals, mainly excitotoxicity but also oxidative stress and glial activation. By contrast, intermediate and, in particular, advanced stages of parkinsonism characterized by a profound nigral degeneration and occurrence of major parkinsonian symptoms (e.g. bradykinesia), are associated with upregulatory responses of CB1 receptors, possibly CB2 receptors too, and the endocannabinoid ligands for both receptor types. This would explain the motor inhibition typical of this disease and the potential proposed for CB1 receptor antagonists in attenuating the bradykinesia typical of PD. In addition, certain cannabinoid agonists have been proposed to serve as neuroprotective molecules in PD, given their well-demonstrated capability to reduce excitotoxicity, calcium influx, glial activation and, in particular, oxidative injury that cooperatively contribute to the degeneration of nigral neurons. However, the potential of cannabinoid-based medicines in PD have been still scarcely studied at the clinical level despite the existence of solid and promising preclinical evidence. Considering the relevance of these preclinical data, the need for finding treatments for motor symptoms that may be alternative to classic dopaminergic replacement therapy, and the lack of efficient neuroprotective strategies in PD, we believe it is of major interest to develop further studies that allow the promising expectations generated for these molecules to progress from the present preclinical evidence towards a real clinical application.

Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS). The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes. Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies [1]. The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer's disease, multiple sclerosis, Huntington's disease and amyotrophic lateral sclerosis.

The central endocannabinoid system is a neuroactive lipid signalling system in the brain which acts to control neurotransmitter release. The expression patterns of this system throughout limbic regions of the brain ideally situate it to exert regulatory control over emotional behaviour, mood and stress responsivity. A growing body of evidence unequivocally demonstrates that deficits in endocannabinoid signalling may result in depressive and anxiogenic behavioural responses, while pharmacological augmentation of endocannabinoid signalling can produce both antidepressive and anxiolytic behavioural responses. The aim of this review is to summarize current knowledge of the role of the endocannabinoid system in the etiology and treatment of mood and anxiety disorders, such as depression, anxiety and post-traumatic stress disorder. Collectively, both clinical and preclinical data argue that cannabinoid receptor signalling may be a realistic target in the development of a novel class of agent for the pharmacotherapy of mood and anxiety disorders.

Corticotropin releasing factor (CRF) is a neuropeptide that is a major regulator of the hypothalamic-pituitaryadrenal system. Recent findings have shown that CRF exists in extrahypothalamic areas in the brain as well as in the hypothalamus, and extrahypothalamic CRF is also deeply involved in stress responses. Therefore, CRF has been a major target of drug development for treatment of stress-related disorders. However, whether CRF is a cause or a result of fear/anxiety has not been investigated extensively, even though this issue is extremely important to the development of treatments for stress-related disorders. This article aims to 1) introduce readers to several functional aspects of CRF, focusing on aspects that have been missed or ignored when determining the roles of CRF in responses to emotional stress; 2) critically review previous studies regarding the roles of CRF in responses to emotional stress, considering functional aspects of CRF described in 1); and 3) put forward a hypothesis about the roles of CRF in stress responses. Considering different functional aspects of CRF, it is suggested that CRF is a result of fear/anxiety, rather than a cause. In other words, CRF could be responsible for stress responses to cope with dangerous situations but not for fear/anxiety itself. CRF as a potential target of drug development for treatment of stress-related disorders is also discussed.

In the past decade there has been increasing interest in the potential benefit of early pharmacological intervention in schizophrenia. Patients with schizophrenia show nonpsychotic and nonspecific prodromal symptoms (e.g., depression and cognitive deficits) for several years preceding the onset of frank psychosis. Several studies have demonstrated that medication with atypical antipsychotic drugs in people with prodromal symptoms may reduce the risk of subsequent transition to schizophrenia. Furthermore, a naturalistic treatment study in young people with prodromal symptoms demonstrated that medication with antidepressants could prevent the development of psychosis. Although the sample in this study was small, the results were striking. Some antidepressants, including selective serotonin reuptake inhibitors (SSRIs), had high to moderate affinities at the endoplasmic reticulum protein sigma-1 receptors, which are implicated in neuroprotection and neuronal plasticity. Among all antidepressants, fluvoxamine was the most potent sigma- 1 receptor agonist since the effects of fluvoxamine were antagonized by the selective sigma-1 receptor antagonist NE-100. Based on the role of sigma-1 receptors in the pathophysiology of cognition and depression, the author would like to propose a hypothesis that SSRIs (e.g., fluvoxamine) with sigma-1 receptor agonism may reduce the risk of subsequent transition to schizophrenia.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.

Due to the increasing number of data demonstrating a connection between diabetes and Alzheimer's disease (AD), efforts have been developed to elucidate the exact mechanism(s) underlying this connection. Although both disorders possess several overlapping features, mitochondrial dysfunction is one of the most relevant rendering mitochondria an important target of scientific research. This review discusses clinical and biochemical features shared by AD and diabetes, giving special attention to the involvement of mitochondria. The realization that mitochondria are at the intersection of cells' life and death has made them a promising target for drug discovery and therapeutic interventions. Here we also discuss in vitro, in vivo and clinical studies that examined the effect of mitochondria-directed therapeutics particularly mitochondrial target antioxidants and Szeto-Schiller peptides.

Multiple sclerosis (MS) is a chronic, debilitating condition mediated by inflammation and neurodegeneration. The ultimate goal of treatment is to delay or halt the progression of irreversible disability. Disease-modifying drugs (DMDs), including beta interferon and glatiramer acetate during phase III trials, have been shown to reduce relapse rates in relapsing-remitting multiple sclerosis (RRMS) as detected by magnetic resonance imaging (MRI). However, the longterm effects of DMDs on MS progression are not very clear; therefore, the aim of this paper is to evaluate the evidence available of the long-term effects of DMDs on reducing the progression of multiple sclerosis. A number of open-label, prospective extensions that followed a cohort of patients enrolled in double-blind, placebo-controlled trials were examined. Methodological difficulties faced in designing a trial of extended duration were hard to overcome, however, and long-term, open-label extensions of interferon and glatiramer acetate failed to show significant beneficial effects in delaying disability progression, questioning the cost-effectiveness of these therapies in the long-term.