CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 7, Issue 4, 2008

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s disease. In PD' motor symptoms result from the degeneration and loss of pigmented dopaminergic neurons of the substantia nigra pars compacta of the basal ganglia. Other neuronal fields and neurotransmitter systems are also involved, including nonadrenergic, serotonergic and cholinergic neurons. Since the early 1960s the treatment of PD has been based on the pharmacologic replacement of dopamine accomplished with the precursor of dopamine, 3, 4-dihydroxy-L-phenylalanine (L-dopa). The addition of carbidopa, an inhibitor of the decarboxylase represented a tremendous improvement in therapy and is still a mainstay of the treatment of PD. Dopamine agonists may also be used, as well as inhibitors of monoamine oxidase-B or catechol-O-methyltransferase. Other medications include anticholinergics and amantadine. These therapies are only symptomatic and none halt or lessen dopaminergic neuron degeneration and the progression of the disease. This has prompted the search for novel and alternative pharmacological targets and neuroprotective therapies. In this context, there are data to suggest a benefit from glial cell line-derived neurotrophic factor, neuroimmumophlin ligands, minocycline, Coenzyme Q10, creatine, reduced glutathione, adenosine A2A receptor antagonists as well as glutamate release inhibitors. Restorative techniques to compensate for cell loss include tissue transplantation and gene transfer therapy. Due to the paucity of data regarding non-pharmacological approaches such as diet therapy or antioxidant therapy, these await more studies. There are also few studies on medicinal plants. Other areas of increasing importance would thus include the investigation of active constituents of plants and phytomedicines with a view to the discovery of new compounds. Finally, stem cell therapy may offer the promise of restoring functionality.

Advances in the understanding of mechanisms underlying the pathophysiology of epilepsy have led to the identification of sodium hydrogen exchanger (NHE) as one of the possible targets for future antiepileptic drugs (AEDs). There are indicators from several experimental studies that NHE inhibitors could be of significant value as potential anticonvulsants. Various in-vitro reports (brain slices) have suggested anticonvulsant potential of these agents. Recently we provided the in-vivo data on anticonvulsant efficacy of amiloride (an NHE inhibitor) in different animal models of seizure and epilepsy. In addition to blocking NHE, these agents are known to affect other traditional targets like voltage-gated Na+ channels, Ca2+ channels, glutamate concentration, etc. Thus NHE inhibitors may represent a novel class of AEDs and surely deserve more scientific attention. In this review, we focus on the role of NHE in epilepsy and provide the experimental evidence available so far on the effect of NHE inhibitors in various animal models.

The role of Glutamate (Glu), one of the major excitatory neurotransmitters in the central nervous system, has been thoroughly investigated in animal models and in humans in several physiologic events, such as brain development and synaptic plasticity, but also in acute and chronic neurologic diseases and psychiatric disorders. Recently, it has been demonstrated that Glu is important for sensory input transduction, particularly along the nociceptive pathway. Glu involvement in peripheral neuropathies has also been suggested on the basis of experimental studies in animals, thus widening the spectrum of possible sites of action of this neurotransmitter from the central to the peripheral nervous system. This rather unexpected observation may have important therapeutic implications, provided that a complete characterization of the glutamatergic system in the peripheral nervous system is achieved and its changes under the different pathological conditions are investigated. This review will focus on the most recent advances in the research into the role of Glu and the glutamatergic system in the pathology of the peripheral nervous system.

Adult stem cell therapy has been proposed for brain injury in young children. While there have been no clinical trials in the US, the therapy is widely advertised and anecdotally reported in multiple internet sources, leading families to seek the treatment in uncontrolled circumstances. The purpose of this review is to present a discussion of the various types of stem cell preparations, with emphasis on adult stem cells, the scientific basis of their development, and the available experimental evidence for their utility in childhood brain injury. We will also provide background information on the biologic events occurring in injured immature brain, as they relate to the transplantation of stem cells. We will then review our own data from neonatal rodent studies with experimental hypoxic-ischemic brain injury. We have shown that early intracerebral administration promotes improved behavioral outcome in the animals, the formation of new neurons, and the preservation of intrinsic cells. New experiments demonstrate the equality of intracerebral and intravenous transplantation in acute neonatal hypoxic-ischemic injury in rodent. We will speculate on the possible clinical uses of adult stem cells. Our current impression is that the cells have the greatest potential for success when administered soon after an injury. What needs to be done to further the field? The different types of cell preparations should be tested against each other in experimental situations. A suitable model of chronic brain injury should be utilized for evaluating the benefit of the cells for this purpose. Long term safety of the cells should be confirmed in animal models. Finally, multicenter clinical trials should be conducted in highly controlled protocols.

Transglutaminases are a large family of related and ubiquitous enzymes which catalyze the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other reactions important for the cell viability. The distribution and the physiological roles of the human transglutaminases have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified. Recently, “tissue” transglutaminase (TG2) has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD). Transglutaminase activity has also been hypothesized to be directly involved in the pathogenetic mechanisms responsible for several human neurodegenerative diseases, which are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains, such as Alzheimer's disease (AD), Parkinson's disease (PD), supranuclear palsy, Huntington's disease (HD) and other recently identified polyglutamine diseases. In this review we discuss the biochemistry of the transglutaminases, with particular reference to the molecular mechanisms that could be involved in the physiopathological processes responsible for these human neurodegenerative diseases.

Minocycline, an antibiotic of the tetracycline family, has been shown to display neurorestorative or neuroprotective properties in various models of neurodegenerative diseases. In particular, it has been shown to delay motor alterations, inflammation and apoptosis in models of Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease. Despite controversies about its efficacy, the relative safety and tolerability of minocycline have led to various clinical trials. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline as an open-label adjunct to antipsychotic medication to patients with schizophrenia. The results of this trial suggested that minocycline might be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for “boosting” antipsychotic efficacy and for treating schizophrenia. The present review summarizes the available data supporting the clinical testing of minocycline for patients with schizophrenia. In addition, we extend our discussion to the potential applications of minocycline for combining this treatment with cellular and molecular therapy.

A variety of sublethal or stressful stimuli induce a phenomenon in the brain known as tolerance, an adaptive response that protects the brain against the same stress, or against a different stress (cross-tolerance). Understanding the molecular mechanisms of brain preconditioning holds promise in developing innovative therapies to prevent and treat neurodegenerative disorders, particularly ischemic stroke. Many of the detailed steps involved in tolerance and crosstolerance are unknown. It is also likely that different stressors differentially regulate sets of genes, transcription factors, and signal transduction pathways that depend upon the molecules that are released in response to the stressor, activation of particular receptors, and the surrounding milieu. The focus of this review is to highlight a few examples of stimuli that induce tolerance: 1) cortical spreading depression; 2) 3-nitropropionic acid; and 3) 2-deoxy-D-glucose. We will summarize by discussing one pathway where intracellular mediators may converge to upregulate intrinsic neuronal survival pathways to promote survival by resisting damage. This mechanism, activation of N-methyl-D-aspartate receptors and its integral relationship with brain-derived neurotrophic factor, may be a critical and general mechanism developed in brain to respond to stressful stimuli.