Recent Patents on CNS Drug Discovery (Discontinued) - Volume 3, Issue 3, 2008

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.

The gap between basic neuroscience and clinical psychiatry in the treatment of anxiety disorders has been steadily diminishing over recent years. Among the leading advances in this field of translation research is the application of knowledge on the neurobiology of fear memory to the treatment of anxiety disorders in humans. Animal studies have identified N-methyl-D-aspartate (NMDA) receptors as crucial in fear memory acquisition and consolidation, as well as in its extinction and reconsolidation. Based on this, the NMDA receptor partial agonist D-cycloserine, which facilitates fear extinction in rodents, has been shown to increase the effect of exposure therapy in psychiatric patients for conditions such as phobias, social anxiety and obsessive-compulsive disorder. In this article, we review current strategies for targeting the NMDA receptor in the treatment of fear-related disorders, analyzing experimental results, clinical data, and recent patents in the field, while also addressing potential new approaches to explore this field of drug discovery.

High-grade primary and metastatic central nervous system (CNS) tumors are common, deadly, and refractory to conventional therapy and have a median survival duration of less than one year. A key transcriptional factor, signal transducer and activator of transcription (STAT) 3, drives the fundamental components of tumor malignancy and metastases in the CNS. STAT3 promotes this tumorigenesis by enhancing proliferation, angiogenesis, invasion, metastasis, and immunosuppression. The clinical implementation of drugs that specifically target malignancy within the CNS is clearly a major unmet need. A group of potent, small molecule inhibitors of STAT3 display marked efficacy with minimal toxicity against malignancy in murine models, including established intracerebral tumors. The mechanism of this in vivo efficacy of the STAT3 blockade agents is a combination of direct tumor cytotoxicity and immune cytotoxic clearance. Given their ability to achieve good CNS penetration, these drugs will be taken forward into clinical trials for patients with CNS malignancies and as immunotherapeutic enhancers.

Spinal cord injury leads to a devastating cascade of secondary complications that eventually results in the formation of scar tissue many times the size of the original insult. Inflammation plays a very important role towards the development of such scar, but paradoxically, at the same time it has neuroprotective properties. Only recently have we understood enough about the relevant events to make the repair of injured spinal cords a reachable goal. Over the past decade, researchers have designed and tested numerous innovative therapeutic strategies, and many of such involve manipulation of the immune response. Interestingly, both immuno-stimulatory and immuno-suppressive interventions have shown positive results, which include the prevention of further tissue damage, prevention of secondary cell death and axonal degeneration, promotion of remyelination, stimulation of axonal regeneration, and facilitation of sensorimotor function recovery.

Small molecule modulators of neural stem cell (NSC) differentiation might potentially be developed into orally administered neurogenic drugs to treat neurodegenerative diseases including Alzheimer's disease. New technologies developed for the study of NSC culture, proliferation and differentiation have enabled the establishment of screening platforms to identify small molecules with neurogenic activity. Recent patents claim novel small molecules identified from screening collections that stimulate or otherwise regulate stem cell differentiation and neurogenesis. Several patents claim newly discovered NSC differentiation modulating activity of previously marketed drugs suggesting perhaps a previously unknown mechanism of action of these drugs and/or implicating the target enzyme and receptor pathways as key players in neurogenesis. This relatively new area of research into small molecule modulators of neurogenesis is reviewed and recent patents claiming small molecule neurogenic compounds, potentially orally administered CNS regenerative therapies are summarized.

Gap junctions (GJs) are highly specialized membrane structures which allow the passage of small molecules and ions between neighboring cells. Intercellular communication via GJs is a crucial mechanism that plays a central role in several pathologies. This review focuses on: i) the role of connexins (Cxs, transmembrane proteins that form GJ channels) in the pathophysiology of neuronal injury after brain hypoxia-ischemia, ii) the opposing theories regarding whether Cxs are protective agents or contribute to the spread of damage, and iii) recent patent applications and registrations showing Cxs as key targets in regulating GJ-mediated intercellular communication.

The brain is one of the least accessible organs of the body, thus making the delivery of neurotherapeutics almost a challenge. Despite its relatively high nutrient support and exchange requirements, the uptake of any compound is strictly regulated by the blood brain barrier (BBB). As a consequence, BBB prevents effective treatment of many severe and life threatening diseases like brain cancer, epilepsy, Alzheimer's disease, schizophrenia etc. Numerous drug delivery strategies have been developed to circumvent this barrier. One such approach is the use of nanoparticles. Nanoparticles form solid, colloidal drug delivery system that consists of macromolecular materials in which the active principle is dissolved, entrapped or encapsulated or onto which the active principle is adsorbed or attached. Brain targeted polymeric nanoparticles have been found to increase the therapeutic efficacy and reduce the toxicity for a large number of drugs. By coating the nanoparticles with surfactants, higher concentrations of drugs can be delivered to the brain. The article presents various approaches used in design and delivery of nanoparticles to brain. It also reviews various patents that describe the use of nanoparticles to deliver various neurotherapeutics and neurodiagnostics to brain.

Neurological/neuropsychiatric complications are commonly observed after heart surgery. They include the cerebral ischemic episode, transient ischemic attack, postoperative cognitive decline and postoperative delirium. In this review article, we are dealing with the etiology of these complications, mainly focusing on the role of genetic components. We are also commenting on the putative role of certain pharmacologic agents in the treatment of the aforementioned nosological entities.

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