CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 10, Issue 6, 2011

Post-transcriptional regulation represents a powerful means to exert control over gene expression and to enhance plasticity and adaptability at the molecular, cellular and functional levels, even in a complex organ such as the nervous system. Approximately 80% of the human brain genome is transcribed into RNA, yet only about 2% of the genome is transcribed into protein, which emphasizes the capability of various steps of RNA signalling and RNA-based mechanisms to contribute to gene control. In this regard, one of the hottest research topics in biology today is the nuclear processing and cytoplasmic formation of microRNAs (miRNAs) that occur in all eukaryotic cells. miRNAs are small, noncoding portions of ribonucleic acid binding to the 3'-untranslated region of target mRNAs and leading to translational repression or degradation of the target. Since the requirement for target complementarities is only partial in eukaryotic cells, one miRNA can potentially have hundreds of targets, and each mRNA can be regulated by many miRNAs. Because there are almost 16,000 miRNAs in animals, plants, and viruses, and more than 1000 different known human miRNA sequences (each of approximately 20-25 nucleotides), exact prediction of the actual mRNA targets would appear to lie just beyond our grasp. At least 20-30% of human protein-coding genes are likely controlled by miRNAs. Recent studies have demonstrated that miRNAs are key regulators of diverse biological processes, such as cell proliferation, growth, differentiation and apoptosis. A growing body of evidence indicates that miRNAs are highly expressed in the CNS with several being found specifically in brain, where they play important roles in normal and/or pathological development and functioning. For instance, miRNAs have a role in brain morphogenesis, neurogenesis, neuronal differentiation, dendritic spine generation, synaptic formation and plasticity. In addition, some miRNAs have been implicated in neuropsychiatric disorders, epileptic seizures, traumatic spinal cord and brain injuries, brain cancer and ischemia, Parkinson's, Alzheimer's, and Huntington's diseases, Rett, Fragile X and Tourette's syndromes. Although certain factors such as the genome itself, stress, RNA oxidation, lack of neurotrophic proteins and environmental influences have been identified as possible determinants of changes in miRNAs expression, we are only now beginning to understand the impact of this novel class of gene regulators on the CNS. Identifying the complex roles of miRNAs and their targets thus promises to bring new insights to many aspects of neuronal function and dysfunction, and to be decisive for future research, by fostering potential application of miRNAs as biomarkers, diagnostic instruments and therapeutic tools for many neurodegenerative and neuroinflammatory diseases. Giving strength to this idea, a study recently published in Science by Williams and co-authors describes that microRNA-206 (miR-206), a skeletal muscle-specific miRNA that is dramatically induced in a mouse model of Amyotrophic Lateral Sclerosis (ALS) in coincidence with the onset of neurological symptoms, is a modifier of disease pathogenesis. ALS is characterized by progressive degeneration of all upper and lower motor neurons, denervation of target muscles, atrophy, paralysis, and finally death due to respiratory failure. There is currently no effective treatment for ALS and identification of the specific cellular mediators, especially the bidirectional signalling between motor neurons and skeletal muscles at the neuromuscular synapse, remains a major challenge in the search for novel and successful therapeutics. In order to distinguish if the increased level of miR-206 in ALS might be an innocuous correlate, a contributor to pathology, or part of an ultimately inadequate compensatory effort, Williams and colleagues generated targeted mutants in which miR-206 expression is abolished in mice expressing G93A-SOD1 (a mutation in the ubiquitous free radical scavenger enzyme Cu,Zn superoxide dismutase, that is the most frequent cause of familial ALS). Loss of miR-206 didn't apparently affect disease onset, but rather accelerated its progression. Exacerbation of disease symptoms in miR-206-/- ALS mice was accompanied by skeletal muscle atrophy, kyphosis, paralysis, and diminished survival by about one month. The notion that motor neuron pathology plays a key role in ALS, whereas miR-206 is present exclusively in muscles, led Williams and co-authors to speculate that the miRNA might affect nerve-muscle interactions. They then sought to prove that reinnervation of denervated muscles by motor axons is delayed in the absence of miR-206, without impairment of axonal regeneration. The authors demonstrated that miR-206-/- / G93A-SOD1 neuromuscular junctions are disorganized, showing deficient colocalization of nerve and postsynaptic sites. Next they asked how miR-206 might promote a partially successful compensatory response to denervation in ALS. Using reporter constructs, the Science paper goes on to demonstrate that one role of miR-206 is to repress the translation of histone deacetylase 4 (HDAC4) mRNA, the strongest computationally predicted target of miR-206, also implicated in the control of neuromuscular gene expression. Furthermore, the skeletal muscle phenotype of HDAC4 null mice was opposite that of miR-206-/- mice, in terms of reinnervation following injury. As predicted for a miRNA and its substrate, this result suggests that miR-206 and HDAC4 might have contrasting effects on retrograde signals required for reinnnervation, and that miR-206 might function to counteract the negative influence of HDAC4. In search of muscle-derived synaptic organizing factors that are affected in a contrary way by miR-206 and HDAC4, the authors next proved that fibroblast growth factor binding protein 1 (a secreted factor interacting with fibroblast growth factor family members to potentiate their bioactivity) is significantly down-regulated following denervation in miR-206-/- mice, but up-regulated in HDAC4 skeletal muscle knockout mice. The consequent implication is that the salutary actions of miR-206 are mediated by muscle-derived factors that sustain nerve-muscle interactions in response to motor neuron injury, and that miR-206 slows ALS progression by sensing motor neuron injury and promoting compensatory regeneration of neuromuscular synapses.

As a relatively common neurodegenerative disease associated with aging, Parkinson's disease (PD) impacts increasing numbers of people as population structures are shifted towards older individuals. For many people living with PD, the disease process leads progressively to increased disability and lowered quality of life. Many of the cardinal symptoms in PD relate to impairment of normal fluid movement, but as the disease progresses more of the brain is involved such that at the later stages it is not uncommon for higher cortical functions to be damaged. Overall, this makes treating PD a complex issue but an important one for people living with the disease and for their caregivers and families. The articles collected in this special edition of CNS & Neurolgical Disorders - Drug Targets generally address two different issues that relate to the treatment of PD. The first is the current status of symptomatic treatments. Many, but not all, of the movement problems in PD are well treated in the early stages of the disease, most famously with the use of L-DOPA, the precursor for the neurotransmitter dopamine. For many patients, L-DOPA is effective, safe and restores movement for several years although it does not address all the neurological symptoms in PD and can become less effective over time and has some side effects such as dyskinesia. L-DOPA is not covered in this volume as it has been addressed in depth in many previous reviews and monographs, but treatments based around other neurotransmitter systems or using nonpharmacological approaches are discussed. It is critical to keep developing treatments for the variety of symptoms in PD, to provide a better armamentarium for clinicians and to find ways to maintain benefit while minimizing side effects. To the latter end, treating the side effects themselves is also important, as shown in this volume by the discussion of the basic biology of dyskinesias and identification of new ways to address this problem. But, there is a second issue that will be addressed in this volume, and that is how to treat the underlying disease process as well as the symptoms. Ideally, we would like to halt or even reverse the progressive nature of PD perhaps at the stage of mild, tolerable movement problems, which again underscores the need for improved symptomatic treatments. Treating the underlying progressive pathophysiology is difficult in most neurodegenerative conditions and such disease modifying-therapies remain an unmet ideal for drug development. But, there are several ways in which we could think about drug targets where the promise of modifying the disease could one day be met. Those relate to better understanding of the underlying causes of PD. One of the recent revolutions in thinking about PD, and many other neurodegenerative diseases, has come from the recognition that genetics explains at least some of the lifetime risk of disease in families but also in apparently sporadic disease. It follows, therefore, that understanding the molecules that contribute to genetic risk of disease might lead us to a better understanding of disease process and hence to new targets for modifying disease and this will be discussed in some of the collected articles here. Also, understanding the basic biology of the nervous system can be used to identify neuroprotective pathways, and the possibility of using trophic factors to treat PD is also covered in this collection....

A promising target for improved therapeutics in Parkinson's disease is the nicotinic acetylcholine receptor (nAChR). nAChRs are widely distributed throughout the brain, including the nigrostriatal system, and exert important modulatory effects on numerous behaviors. Accumulating evidence suggests that drugs such as nicotine that act at these sites may be of benefit for Parkinson's disease treatment. Recent work indicates that a potential novel therapeutic application is the use of nicotine to reduce levodopa-induced dyskinesias, a side effect of dopamine replacement therapy for Parkinson's disease. Several clinical trials also report that nicotine may diminish disease symptoms. Not only may nAChR drugs provide symptomatic improvement, but they may also attenuate the neurodegenerative process itself. This latter idea is supported by epidemiological studies which consistently demonstrate a ∼50% reduced incidence of Parkinson's disease in smokers. Experimental work in parkinsonian animal models suggests that nicotine in tobacco may contribute to this protection. These combined findings suggest that nicotine and nAChR drugs offer the possibility of improved therapeutics for Parkinson's disease.

Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A2A receptors (A2ARs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D2 receptor (D2R). Furthermore, it is assumed that the formation of balanced A2AR/D2R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A2AR activation reduces the affinity of striatal D2R for dopamine and the blockade of A2AR with specific antagonists facilitates function of the D2R. Thus, it may be postulated that A2AR antagonists are pro-dopaminergic agents. Therefore, A2AR antagonists will potentially reduce the effects associated with dopamine depletion in Parkinson's disease (PD). Accordingly, this class of compounds have recently attracted considerable attention as potential therapeutic agents for PD pharmacotherapy as they have shown potential effectiveness in counteracting motor dysfunctions and also displayed neuroprotective and anti-inflammatory effects in animal models of PD. Overall, we provide here an update of the current state of the art of these A2AR-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.

There has been renewed interest in the surgical treatment of Parkinson's disease (PD) over the past 20 years. In the 1940's to 1960's many PD patients underwent neurosurgical procedures to ablate specific brain targets to alleviate tremor and, to a lesser extent, akinesia and rigidity. With the introduction of levodopa in the 1960s, and the realization of its striking benefits, surgical treatment of movement disorders virtually disappeared. With time, limitations and adverse effects associated with drug treatment became all too apparent. With complications associated with long-term drug treatment, particularly levodopa-induced motor fluctuations and dyskinesias, limiting therapeutic effectiveness in many patients, surgery has been reexamined to address this unmet need. This has lead to the development and, now, widespread adoption of high-frequency deep brain stimulation (DBS). DBS has been shown to be a safe and effective treament for dopaminergic motor symptoms of PD, particularly tremor, rigidity, and bradykinesia, and has resulted in important reductions in motor complications of medical therapy. While DBS provides important symptomatic benefit, it does not appear to alter the natural history of PD. Other surgical strategies, including cellular transplantation and gene therapy aiming at neural repair and restoration, are currently being examined, but these have yet to be proven useful.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure whereby a pulsed magnetic field stimulates electrical activity in the brain. Parkinson's disease (PD) is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Consequently, more advanced non-invasive therapeutic methods are required. A possible method of rehabilitation that may be effective and potentially viable for use in clinical practice is rTMS. Here, we focus on the basic foundation of rTMS, the main findings of rTMS from animal models, the effects of rTMS on sensorimotor integration in patients with PD, and the experimental advances of rTMS that may become a viable clinical application to treat the disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction that occurs secondary to loss of dopaminergic neurons in the nigrostriatal pathway. Current pharmacotherapies focus on the replacement of lost dopamine to alleviate disease symptoms. However, over time this method of therapy loses effectiveness due to the continued death of dopaminergic neurons. Alternative strategies for the treatment of PD are aimed at modifying the disease state through the preservation of remaining dopamine neurons or even the regeneration of dopamine innervation through the use of neurotrophic factors. Neurotrophic factors are specialized proteins that can promote neuronal development, maintain neuronal health and modulate neuronal function in the ventral midbrain, making them candidates for the treatment of PD. Preclinial studies indicate that members of the glial cell line-derived neurotrophic factor family of ligands are capable of preserving the degenerating dopamine neurons. These promising results moved neurotrophic factor therapy to clinical trials in PD patients. To date, neurotrophic factor therapy is proven to be safe and well-tolerated in humans, but conclusive evidence of efficacy in the clinic remains to be determined. This review will discuss the preclinical and clinical experiments of glial cell line-derived neurotrophic factor family ligands for the treatment of PD.

One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded αsyn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.

Intense research efforts are currently directed at elucidating the etiology of Parkinson's disease (PD). One approach that has begun to shed light on the PD pathogenic pathways is the identification of disease genes through genetic linkage or association studies. These studies have revealed that several kinases may be involved in PD, as some PD genes encode kinases themselves while other PD genes are found in the same cellular pathways as kinases. Two of these kinases stand out as potential drug targets for novel PD therapy, namely leucine rich repeat kinase 2 (LRRK2) and the alpha-synuclein (α-syn) phosphorylating polo-like kinase 2 (PLK2). Indeed, both α- syn and LRRK2 show genetic linkage as well as genetic association with PD, indicating their relevance to a large number of PD cases. Also, due to the dominant mode of α-syn and LRRK2 inheritance and based on current knowledge of LRRK2 and α-syn phosphorylation by PLK2, inhibition of LRRK2 and PLK2 may constitute a potential therapy for PD. Here we discuss the function of these kinases as well as progress in their validation as drug targets for the treatment of PD.

Stroke causes a devastating insult to the brain resulting in severe neurological deficits because of a massive loss of different neurons and glia. In the United States, stroke is the third leading cause of death. Stroke remains a significant clinical unmet condition, with only 3% of the ischemic patient population benefiting from current treatment modalities, such as the use of thrombolytic agents, which are often limited by a narrow therapeutic time window. However, regeneration of the brain after ischemic damage is still active days and even weeks after stroke occurs, which might provide a second window for treatment. Neurorestorative processes like neurogenesis, angiogenesis and synaptic plasticity lead to functional improvement after stroke. Stem cells derived from various tissues have the potential to perform all of the aforementioned processes, thus facilitating functional recovery. Indeed, transplantation of stem cells or their derivatives in animal models of cerebral ischemia can improve function by replacing the lost neurons and glial cells and by mediating remyelination, and modulation of inflammation as confirmed by various studies worldwide. While initially stem cells seemed to work by a ‘cell replacement’ mechanism, recent research suggests that cell therapy works mostly by providing trophic support to the injured tissue and brain, fostering both neurogenesis and angiogenesis. Moreover, ongoing human trials have encouraged hopes for this new method of restorative therapy after stroke. This review describes up-to-date progress in cell-based therapy for the treatment of stroke. Further, as we discuss here, significant hurdles remain to be addressed before these findings can be responsibly translated to novel therapies. In particular, we need a better understanding of the mechanisms of action of stem cells after transplantation, the therapeutic time window for cell transplantation, the optimal route of cell delivery to the ischemic brain, the most suitable cell types and sources and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment. An integrated approach of cell-based therapy with early-phase clinical trials and continued preclinical work with focus on mechanisms of action is needed.

Multiple sclerosis (MS) is a chronic disease of the central nervous system with not yet completely understood pathogenesis. The so called “chronic cerebrospinal venous insufficiency (CCSVI) theory” has recently emerged, supporting the concept of a cerebrospinal venous drainage impairment as the cause of MS. Since the first publication on this topic with a claimed 100% specificity and sensitivity of the condition for MS diagnosis, CCSVI theory has generated a scientific and mass media debate with a great hope for the miracle of a new possible endovascular treatment of MS (“liberation procedure”). We critically summarize the available evidence on CCSVI discussing inconsistent and incomplete replication of the original results by different groups, methodological limitations and potential therapeutic implications. We conclude that the available data are insufficient to establish conclusively a clear relationship between MS and CCSVI and do not support the role of CCSVI as the primary cause of MS. Until credible scientific evidence replicates the original results, any proposed invasive treatments of CCSVI should be discouraged.