CNS & Neurological Disorders - Drug Targets - Volume 8, Issue 3, 2009

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, with highly variable clinical course that most typically exhibits a relapsing-remitting pattern. Neuroimaging, pathological findings and response to available therapies are also not uniform. It commonly affects young adults and is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. The clinical course of MS is defined as relapsing-remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS) and secondary progressive (SPMS). The treatment of RRMS is based on the use of immunosuppressive and immune-modulating therapy. Immunosuppressive agents have been used in multiple sclerosis for decades. Intravenous methylprednisolone is currently the treatment of choice for the relapses. The currently approved treatments for MS are disease-modifying agents, which only reduce the attack rate and delay progression in some patients and are believed to be effective only for the inflammatory component of the disease. Immunomodulating and immunosuppressive treatments are directed against the inflammatory process and are only partially effective. In RRMS, positive effects on disease activity have slowed disability progression, but in PPMS the same degree of effect of immunotherapies on relapses and active MRI lesions had little or no effects on the progression of disability. This partial failure could be explained by mechanisms of axonal damage at least partially independent from acute or chronic inflammation. This suggests that there is a need for better use of available treatments and the necessity of alternative new therapeutic options to stop disease progression and improve recovery mechanisms. The practicing neurologist must understand the MS spectrum and evaluate patient-specific factors to determine the best strategy for therapy.

Neuropathic pain is a phenomenon characterized by a high population prevalence by possessing several etiologies. In contrast to nociceptive pain, painful signals in neuropathic pain are originated in the nervous system, present poor responses to conventional treatments and may worsen the quality of life. Antiepileptic drugs are increasingly used for different purposes including migraine, neuropathic pain, tremor or psychiatric disorders and they have started to be called neuromodulators. These drugs may act on very different targets such as sodium, potassium or calcium channels, purinergic, GABAergic, glutamatergic or vanilloid receptors and different cytokines including IL-6 or TNF, each if which may be important in managing some aspects of neuropathic pain. Antiepileptic drugs have demonstrated effectiveness in the treatment of this pathology, and owing to the important development of these drugs in the last years, they may become a very effective tool. On the other hand, the increasing knowledge of the pathophysiology of nociception is leading to new channels and receptors as potential targets for treatment. In this paper we try to review the different potential therapeutic targets and role of antiepileptic drugs in the treatment of this pathology.

Background: Gliomas and in particular high-grade gliomas (HGG) demonstrate when compared to other nonneural solid cancers amongst the highest levels of tumor angiogenesis (the formation of new blood vessels from preexisting vasculature). Methods: Angiogenesis is a common theme in cancer biology and reflects the requirement of a vascular network to support continued uncontrolled cancer growth. Early recognition of this paradigm suggested a potential and novel cancer treatment target that led to the discovery and implementation of antiangiogenic therapies. Two basic strategies of cancer antiangiogenic therapy have emerged, one targeting vascular endothelial growth factor, VEGF (growth factor ligandbased antagonists) and the second targeting the vascular endothelial growth factor receptor, VEGFR (receptor-based antagonists, small molecule tyrosine kinase inhibitors). Emerging literature suggests efficacy of antiangiogenic therapy for recurrent HGG. Results: Notwithstanding the limited literature regarding the treatment of recurrent HGG with antiangiogenic therapy (predominantly ligand-based and administered in conjunction with cytotoxic chemotherapy), this therapy has become the de facto standard of care for many. Response rates vary from 30-60% and 6-month progression free survival varies from 25-50%. Problematic however are new antiangiogenic class side effects (hypertension, fatigue, proteinuria, intratumoral hemorrhage, arterial thrombosis and wound dehiscence), timing in relationship to surgery, measurements of response, lack of established dose response relationships and pharmacoeconomics and a possible change in tumor biology. Conclusions: Ligand-based antiangiogenic therapy (in particular bevacizumab) is a compelling new targeted therapy for HGG and will continue to emerge as an important novel anti-glioma therapy. Further studies are required to define the population of patients with HGG in whom this therapy is of benefit, identify the optimal dose and schedule, better characterize the value of co-administered (cytotoxic and targeted) therapies and establish validated response measures.

The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

Polymer based therapies offer many potential advantages in the treatment of diseases of the nervous system, and would allow delivery of therapeutic agents directly to the relevant area of brain, circumventing obstacles presented by the blood brain barrier, avoiding the side-effects often associated with systemic medication administration, and permitting much smaller doses of medication. As improvements in diagnostic procedures, particularly imaging, now provide very accurate localization of therapeutic targets in many of these conditions, it is technically feasible to deliver such agents precisely to the relevant brain region. Combined with advances in polymer sciences, there is renewed interest in focal drug delivery systems, particularly around intelligent or controlled release systems which would extend the life-span of these devices considerably. Major obstacles remain, however, particularly around the safety and biocompatibility of such materials, and the complexity of testing in clinical scenarios. We review here the current status of animal and human studies in this rapidly evolving area, addressing some of the practical obstacles and examining the range of potential applications in chronic neurological disease.

Tetracyclines are a class of antibiotics which could play a therapeutic role in several neurological disorders. Minocycline, extensively studied in animal models, decreased the size of ischaemic and haemorrhagic infarct. In Parkinson's disease models minocycline protected the nigrostriatal pathway, and in Huntington's disease and motoneuron disease models delayed the progression of disease extending the lifespan. Finally, in human diseases such as stroke and multiple sclerosis tetracyclines seem to play some neuroprotective role. The main biological effects of tetracyclines are the inhibition of microglial activation, the attenuation of apoptosis, and the suppression of reactive oxygen species production. These mechanisms are involved in the pathogenesis of several neurodegenerative disorders. Several reports showed that minocycline reduced mitochondrial Ca2+ uptake, stabilized mitochondrial membranes, and reduced the release into the cytoplasm of apoptotic factors. Other effects include upregulation of mitochondrial bcl-2 (an antiapoptotic protein), direct scavenging of reactive oxygen species, and inhibition of mitogen activated protein kinases. It is still unclear which of these mechanisms plays the pivotal role in neuroprotective properties of tetracyclines. The anti-apoptotic effect of tetracyclines probably involves the mitochondrion. The major target for tetracyclines in neurodegeneration could lie within the complex network that links mitochondria, oxidative stress, poly (ADP-ribose) polymerase-1 and apoptosis. Here, we review the neuroprotective effects of tetracyclines in animal models and in human disease, and we focus on their possible mechanism(s) of action, with special regard to mitochondrial dysfunction in neurodegeneration.