oa Editorial [Hot Topic: Novel Therapeutic Strategies in Neural Diseases Uncover Unexpected Disease Connections: From Neurodegeneration and Addiction to Pain and Depression (Guest Editor: Gonzalo Herradon)]

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....