CNS & Neurological Disorders - Drug Targets - Volume 6, Issue 6, 2007

Neurons are typically post-mitotic cells. This means that they are expected to have a life span comparable to that of their carriers. Unfortunately, sometimes, they die prematurely as a result of complex processes known as “neurodegeneration”. Neurodegenerative diseases are now generally considered a group of disorders that seriously and progressively impair the functions of the nervous system through causing the selective neuronal vulnerability of specific brain regions. Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer Disease (AD), Multiple Sclerosis (MS), and prion disease represent several distinct categories of disease and each manifests its own unique symptoms. However, the diseases share several common features, particularly the aggregation and deposition of abnormal proteins. Neurodegenerative disorders are associated with high morbidity, and few or no effective treatments have been available until now. Neurodegenerative diseases represent a threat to mankind in a variety of guises and induce chronic suffering and debilitation in about 2% of the worldwide population. Moreover, the increase in lifespan of western populations will mean that these neurodegenerative diseases will become more common. Consequently, it is estimated that the number of PD patients will double to between 8.7 and 9.3 million by 2030. As a group, these disorders are a major burden on health care systems compared with other causes of death and the costs of treatment are expected to rise sharply. Despite the enormous amount of progress we have made in terms of understanding the aetiologies of these diseases in the last few years, important questions remain unanswered. This special number deals with this hot topic and is produced by leading groups in the neuroscience field with the aim of summarizing recent advances in genetic, epideniological, molecular and cellular biology research that have increased our knowledge of the mechanisms that give rise to degenerative processes and, in general, to alterations of the structure and function of the nervous system. These contributions give insight into new pharmacological therapies for their treatment and review new and old drugs aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. The pharmaceutical industry faces arguably its most difficult challenge in attempting to develop therapeutics for neurodegenerative disease. The development of disease-modifying therapeutics that addresses the principal causes of neurodegenerative disease is still in its infancy. de Lago and Fernandez-Ruiz provide an extensive description of the neuroprotective properties of cannabinoids. They focus their review on the cellular and molecular mechanisms through which cannabinoids might arrest/delay the degeneration of specific neuronal subpopulations in neurodegenerative disorders such as PD, HD, multiple sclerosis (MS) and other motorrelated disorders. The potential use of cannabinoid agonists as novel therapeutic options is based on their antioxidant, antiinflammatory and anti-excitotoxic properties that allow them to afford neuroprotection in different disorders. Carnevale et al. review the current information on the reciprocal interactions between glia and neurons that are essential for many critical functions in brain health and disease. Microglial cells, the brain resident macrophages, and astrocytes, the most prevalent type of cell in brain, are actively involved in the control of neuronal activities both in developing and adult organisms. At the same time, neurons influence glial functions, through direct cell-to cell interactions as well as the release of soluble mediators. The authors concentrate on signals from neurons that may have an active role in controlling glial activation on two major neurotransmitters: acetylcholine (Ach) and noradrenaline (NA). The cholinergic and adrenergic anti-inflammatory pathways represent important physiological neuro-immune mechanisms by which the innate and adaptive immune responses are kept in control..........

Neuroprotective properties of cannabinoids have been extensively studied in the last years in different neurodegenerative pathologies. This potential is based on the antioxidant, anti-inflammatory and anti-excitotoxic properties exhibited by these compounds that allow them to afford neuroprotection in different neurodegenerative disorders like Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and others. PD and HD are chronic pathologies that are caused by the degeneration of specific structures within the basal ganglia. In both disorders, the key mechanisms involved in the neuroprotection provided by cannabinoids include cannabinoid receptor-independent effects aimed at reducing the oxidative injury, and also cannabinoid 2 receptors (CB2)-mediated effects exerted by regulating the influence of reactive microglia on neuronal homeostasis. MS is an inflammatory demyelinating disorder primarily affecting spinal neurons and secondarily producing a malfunctioning and/or degeneration of other neuronal subpopulations located in supraspinal brain structures. There is evidence that both cannabinoid 1 receptors (CB1) and CB2 may afford a protective effect in this disease due to their immunomodulatory, anti-inflammatory and anti-excitotoxic properties. Lastly, neuroprotective effects of cannabinoids exerted by the activation of CB1 but also CB2 receptors have been also identified in amyotrophic lateral sclerosis (ALS), another degenerative disease characterized by the selective death of spinal motoneurons. In the present review, we will collect the latest advances in the knowledge of the cellular and molecular mechanisms through which cannabinoids might arrest/delay the degeneration of specific neuronal subpopulations in these motor-related disorders. This should serve to encourage that the present promising evidence obtained mainly at the preclinical level might progress to a real exploitation of neuroprotective benefits of potential cannabinoid-based medicines.

Reciprocal interactions between glia and neurons are essential for many critical functions in brain health and disease. Microglial cells, the brain resident macrophages, and astrocytes, the most prevalent type of cell in brain, are actively involved in the control of neuronal activities both in developing and adult organisms. At the same time, neurons influence glial functions, through direct cell-to-cell interactions as well as the release of soluble mediators. Among signals from neurons that may have an active role in controlling glial activation are two major neurotransmitters: acetylcholine and noradrenaline. Several studies indicate that microglia and astrocytes express adrenergic receptors, whose activation influences the release of pro-inflammatory mediators, controlling the extent of glial reactivity. Acetylcholine receptors are also expressed by glial cells. In particular, microglial cells express the nicotinic receptor α7 and its activation attenuates the pro-inflammatory response of microglial cultures, suggesting that acetylcholine may control brain inflammation, in analogy to what demonstrated in peripheral tissues. Deficiencies of noradrenergic and cholinergic systems are linked to important neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) and it has been suggested that in addition to impairing neuron-to-neuron transmission, noradrenergic and cholinergic hypofunction may contribute to dysregulation of the normal neuron-glia interaction, abnormal glial reaction and, eventually, neurodegeneration. A deeper knowledge of role of cholinergic and noradrenergic systems in controlling neuron-glia interactions may offer new venues for disease treatments.

Kynurenine pathway is gaining more and more attention every day in biomedical research since this catabolic route for tryptophan decomposition is not only implicated in different neurological disorders, but also possesses neuroactive metabolites with different biological properties, such as pro-oxidant and antioxidant regulators. Thus, the intensive research on this metabolic pathway is helping us to understand those mechanisms underlying neurodegenerative events during the occurrence of pathological process in the central nervous system (CNS), thereby allowing the design of potential therapies for those disorders involving excitotoxic, oxidative and inflammatory components. Here we intend to provide a brief overview on the relevance of this route for several CNS disorders, and discuss recent information on the different biological properties of the neuroactive metabolites of this pathway and their significance for further research.

Neuronal death is a common feature in neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). This occurs over years, not the minutes of classically defined apoptosis, and neurons show both responses of apoptosis and regeneration, evidenced by accumulated oxidative insult and attempts at cell cycle re-entry. There is recent evidence suggesting that several known gene mutations in causing familial AD (amyloid β protein precursor, presenilin-1, or presenilin-2 gene) and familial PD (Parkin, PINK-1, or DJ-1 gene) are associated with increased oxidative stress. Also, several known genetic (e.g. Apolipoprotein Eη4 variant) and environmental (e.g. metals or pesticides exposure) risk factors of sporadic AD and/or PD are associated with increased oxidative stress. In concord, patients at the preclinical stages of AD and PD as well as cellular and animal models of the diseases provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD. In contrast to the general aspects of the pathological hallmarks, aggregation of the disease-specific proteins such as amyloid-β, tau, and α-synuclein may act as a compensatory (survival) response against the oxidative insult via the mechanism that the disease-specific structures sequester redox-active metals. Expanding knowledge of the molecular mechanisms of organism longevity indicates that prolongevity gene products such as forkhead transcription factors and sirtuins are involved in the insulin-like signaling pathway and oxidative stress resistance against aging. An enhancement of the pro-longevity signaling (e.g. caloric restriction) may be a promising approach as anti-oxidative strategy against age-associated neurodegenerative diseases.

Prion diseases are rare fatal neurodegenerative disorders that may either occur sporadically, or be inherited or infectiously acquired in humans. Irrespective of etiology, they can be transmitted to other individuals, this fact being responsible for the public attention prion diseases have received especially since the nineteen nineties, when a new variant of Creutzfeldt-Jakob disease linked to the consumption of prion contaminated beef occurred for the first time in Great Britain. The infectious particle, termed prion, is presumably composed exclusively of a misfolded, partially proteaseresistant conformer (PrPSc) of a normal cell surface protein, the cellular prion protein (PrPC). The pathogenesis of prion diseases comprises entry, spread, and amplification of infectivity in the body periphery in infectiously acquired forms, as well as mechanisms of neuronal cell death in the central nervous system in all disease subtypes. Most experimental therapeutic approaches are either targeted to PrPC or PrPSc, or to the process of conversion from PrPC to PrPSc. Neuroprotective strategies aiming at an interruption of central nervous system pathogenesis have also been tested, albeit with only moderate success. In this review, we discuss actual and potential drug targets in the context of the pathogenic mechanisms of prion diseases.