Current Pharmaceutical Design - Volume 17, Issue 5, 2011

The neurobiology of disease is moving forward at a very rapid pace. Thus, pharmacologists as well as all the broad range of researchers working in the development of new drugs active in neural tissues have to make an extraordinary effort to make Neuropharmacology move as fast as our knowledge of the mechanisms underlying neural diseases grows. For instance, some time ago, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other neurological disorders such as drug abuse, were considered unlinked and, consequently, were treated independently. Less time ago, it could not have been predicted that a health problem of the human kind for centuries like drug addiction shares disease mechanisms with devastating contemporary disorders such as obesity and eating disorders. On the other hand, brain infarction, chronic neuropathic pain and major depressive disorders which may be relevant in the diseases here mentioned are considered untreatable in too many occasions. However, today, we realize that the most successful drug development processes in these fields are those which actively seek to work on the cause, not on the symptoms and, thus, very interesting advances can now be anticipated in the near future to treat the “untreatable”. Therefore, it is considered of critical importance to review and, in some cases uncover, the previously unknown connections between the disease mechanisms underlying neural pathologies with such a high prevalence as those stated above. For instance, reviews included in this issue clearly establish critical roles for a recently discovered family of cytokines, the pleiotrophin/midkine developmentally regulated gene family, in brain infarction, neuropathic pain, drug addiction, Parkinson's disease and Alzheimer's disease. The discoverer of midkine and pioneer of research on this growth factor, Prof. Muramatsu [1], gives an extraordinary overview on the potential of targeting midkine to develop new therapeutics in a wide range of disorders of the nervous system including those cited above. Dr. Ooboshi [2] reviews in a very comprehensive way novel prospects on gene therapy as a useful pharmaceutical intervention to treat stroke, including the use of the midkine gene to limit neural damage caused by brain infarction. Following this path, the important body of evidences underlying the involvement of the other member of this family of cytokines, pleiotrophin, in the development of neuropathic pain is reviewed by Martin et al. [3] who suggest the potential use of this growth factor to treat the cause of neuropathic pain, nerve injury. Interestingly, these neuroprotective roles of pleiotrophin suggested by Martin et al. in neuropathic pain conditions could be the basis for consideration of this growth factor in other neural pathologies involving nerve damage such as Parkinson's disease and drug addiction. In this way, Gramage and Herradon [4] hypothesize different ways of targeting pleiotrophin signaling pathways to potentiate the neuroprotective effects of this growth factor on Parkinson's disease and drug addiction and, more importantly, establish a link between addictive disorders and development of Parkinson's disease. In addition, Alguacil and colleagues [5] review the existing literature establishing the common pathogenic mechanisms underlying drug addiction and eating disorders, proposing as well new therapeutic targets for those diseases. Following with these disorders, it is interesting to note that one of the most limiting factors of the current dopamine replacement therapy in Parkinson's disease is the high prevalence of LDOPA- induced dyskinesias in patients with this neurodegenerative disorder. In this regard, Del Bel and colleagues [6] review the critical role of nitric oxide in dyskinesias developed by patients chronically treated with L-DOPA. Complementarily, Prediger et al. [7] propose an interesting Parkinson's disease animal model with potential advantages to test new compounds developed as new therapeutics for Parkinson's disease, the intranasal administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Another devastating neurodegenerative disorder, Alzheimer's disease, remains today orphan of efficient pharmacological treatments. However, novel prospects based in immunotherapy and clinical trials ongoing in patients with Alzheimer's disease are promising according to the review by Menendez-Gonzalez and colleagues [8]. Finally, a mental disorder, frequently idiopathic, but also often developed as a consequence of all neurological disorders mentioned in this issue, major depression, is reviewed by Vidal and colleagues [9] who focused on modulation of the Wnt-GSK-3-β-catenin pathway, potentiation of endocannabinoid activity and agonism of 5-HT4 receptors as new pharmacological strategies to treat depression. The overall goal of this issue seeks to elucidate what is currently known about these disease connections and how researchers in the field may take advantage of this increasing knowledge in connecting common disease mechanisms to develop new pharmaceutical strategies in the design of new drugs. This issue tries to achieve this goal by discussing how this novel concept of understanding the pathophysiological mechanisms of a priori distant diseases has contributed in the last few years to develop new therapeutic strategies....

Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.

Cerebrovascular disease is the leading cause of death and disability in Japan and most Western countries. Gene transfer techniques may be applicable to the treatment of serious types of stroke, since several experimental studies have revealed the usefulness of gene therapy in the protection of neurons, reduction of infarct size and improvement of function. Prevention of vasospasm after subarachnoid hemorrhage is one of the best candidates for vascular gene therapy. Ischemia-induced apoptosis, inflammation, and derangement of neurovascular units can be targeted by the gene transfer approach. Recent studies have shown that promotion of neurogenesis and functional recovery may also be achieved by this strategy. Furthermore, a combination of stem cell therapy with gene transfer methods may be feasible. This review describes novel approaches for the treatment of stroke using gene transfer techniques.

The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. One rational possibility for the pharmaceutical development of new drugs, including target identification, drug design and evaluation studies, could be to focus on mimicking what organism does to limit nerve damage or to enhance the regeneration of injured axons. Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.

Parkinson's disease (PD) is generally a sporadic disease, and only a small proportion of cases have a clear genetic component. During the last few years, a possible specific cause triggering death of dopaminergic neurons in the substantia nigra, drug of abuseinduced neurotoxicity, is being considered as a potential mechanism to develop PD, especially in the case of abuse of amphetamine and its derivatives. Recent evidences have shown pleiotrophin, a growth factor with important functions in remodeling and repair of injured neural tissue, as an important factor involved in the pathogenesis of both diseases by preventing neurodegeneration in Parkinson's disease, neurotoxicity induced by drug abuse and by its ability to modulate drugs addictive effects. This review discusses targeting growth factors such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) to treat Parkinson’s disease and/or drug addiction and compiles recent evidences to propose the pleiotrophin/receptor protein tyrosine phosphatase β/ζ signaling pathway as a new therapeutic target to treat Parkinson's disease and to prevent drug of abuse-induced neurotoxicity and addictive effects.

Current pharmacological treatments for eating disorders and obesity are of limited value and thus the identification of novel targets is highly needed to enhance the development of more effective drugs. Among the bottlenecks limiting the introduction of new medicines is the reported heterogeneity of these diseases, which makes it difficult to find drugs with broad activity and the lack of animal models with translational validity, especially in the case of anorexia nervosa. Some kinds of obesity and eating disorders can be classified within the pathologies affecting the brain reward system together with drug addiction and others, and therefore specific treatments in these cases can be directed to restore normal function in brain reward pathways. Target identification in this field can greatly benefit from the combined application of genomic/proteomic techniques and robust animal models of reward deficits.

According to classical thinking about Parkinson's disease, loss of dopaminergic input from the substantia nigra pars compacta leads to overactivity and underactivity of the indirect and direct output pathways, respectively, in the basal ganglia. Administration of the dopamine precursor L-DOPA (l-3, 4-dihydroxyphenylalanine) is proposed to induce changes in the opposite directions. L-DOPA is the most used drug to treat Parkinson's disease symptoms. After repeated treatment with this compound, however, disabling secondary effects such as the abnormal involuntary movements usually appear. Nitric oxide is a free radical that can also acts as an atypical neurotransmitter and influences dopamine-mediated neurotransmission. In this paper we will briefly review the role of nitric oxide on motor control and in Parkinson's disease, particularly a possible role of nitric oxide in L-DOPA induced dyskinesia in rodents. Recent results show that nitric oxide synthase inhibition reduces L-DOPA-induced dyskinesia in rats and mice. The effect is dose-dependent, does not suffer tolerance nor interferes with L-DOPA positive motor effects. These preclinical findings suggest that nitric oxide is a promising therapeutic target for the reduction of L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population older than 60 years. Classically, PD is considered to be a motor system disease and its diagnosis is based on the presence of a set of cardinal motor signs that are consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Nowadays there is considerable evidence showing that non-dopaminergic degeneration also occurs in other brain areas which seems to be responsible for the deficits in olfactory, emotional and memory functions that precede the classical motor symptoms in PD. Dopaminereplacement therapy has dominated the treatment of PD and although the currently approved antiparkinsonian agents offer effective relief of the motor deficits, they have not been found to alleviate the non-motor features as well as the underlying dopaminergic neuron degeneration and thus drug efficacy is gradually lost. Another major limitation of chronic dopaminergic therapy is the numerous adverse effects such as dyskinesias, psychosis and behavioral disturbance. The development of new therapies in PD depends on the existence of representative animal models to facilitate the evaluation of new pharmacological agents before they are applied in clinical trials. We have recently proposed a new experimental model of PD consisting of a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1 mg/nostril) in rodents. Our findings demonstrated that rats and mice treated intranasally with MPTP suffer impairments in olfactory, cognitive, emotional and motor functions conceivably analogous to those observed during different stages of PD. Such infusion causes time-dependent loss of tyrosine hydroxylase in the olfactory bulb and SNc, resulting in significant dopamine depletion in different brain areas. We have also identified some pathogenic mechanisms possibly involved in the neurodegeneration induced by i.n. administration of MPTP including mitochondrial dysfunction, oxidative stress, activation of apoptotic cell death mechanisms and glutamatergic excitotoxicity. Therefore, the present review attempts to provide a comprehensive picture of the i.n. MPTP model and to highlight recent findings from our group showing its potential as a valuable rodent model for testing novel drugs that may provide alternative or adjunctive treatment for both motor and non-motor symptoms relief with a reduced side-effect profile as well as the discovery of compounds to modify the course of PD.

Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ1-42 peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ1-42 developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.

Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressants prescribed today, all of them designed to enhance central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy. As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antidepressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development (modulation of the Wnt/GSK-3β/β-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT4 receptors), which involve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms of action, constituting a nexus between the “classic” aminergic theory and the “new” neuroplasticity hypothesis.