Current Neuropharmacology (v.8, #4)

Mesenchymal Stem Cells for Treatment of CNS Injury by Michael F. Azari, Louisa Mathias, Ezgi Ozturk, David S. Cram, Richard L. Boyd, Steven Petratos (316-323).
Brain and spinal cord injuries present significant therapeutic challenges. The treatments available for these conditions are largely ineffective, partly due to limitations in directly targeting the therapeutic agents to sites of pathology within the central nervous system (CNS). The use of stem cells to treat these conditions presents a novel therapeutic strategy. A variety of stem cell treatments have been examined in animal models of CNS trauma. Many of these studies have used stem cells as a cell-replacement strategy. These investigations have also highlighted the significant limitations of this approach. Another potential strategy for stem cell therapy utilises stem cells as a delivery mechanism for therapeutic molecules. This review surveys the literature relevant to the potential of mesenchymal stem cells for delivery of therapeutic agents in CNS trauma in humans.

Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury by Xiyong Fan, Annemieke Kavelaars, Cobi J. Heijnen, Floris Groenendaal, Frank van Bel (324-334).
Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used.

Neuro-psychopharmacogenetics and Neurological Antecedents of Posttraumatic Stress Disorder: Unlocking the Mysteries of Resilience and Vulnerability by Abdalla Bowirrat, Thomas J.H. Chen, Kenneth Blum, Margaret Madigan, John A. Bailey, Amanda Lih Chuan Chen, B. William Downs, Eric R. Braverman, Shahien Radi, Roger L. Waite, Mallory Kerner, John Giordano, Siohban Morse, Marlene Oscar-Berman, Mark Gold (335-358).
Background and Hypothesis: Although the biological underpinnings of immediate and protracted traumarelated responses are extremely complex, 40 years of research on humans and other mammals have demonstrated that trauma (particularly trauma early in the life cycle) has long-term effects on neurochemical responses to stressful events. These effects include the magnitude of the catecholamine response and the duration and extent of the cortisol response. In addition, a number of other biological systems are involved, including mesolimbic brain structures and various neurotransmitters. An understanding of the many genetic and environmental interactions contributing to stress-related responses will provide a diagnostic and treatment map, which will illuminate the vulnerability and resilience of individuals to Posttraumatic Stress Disorder (PTSD). Proposal and Conclusions: We propose that successful treatment of PTSD will involve preliminary genetic testing for specific polymorphisms. Early detection is especially important, because early treatment can improve outcome. When genetic testing reveals deficiencies, vulnerable individuals can be recommended for treatment with and#x201C;body friendlyand#x201D; pharmacologic substances and/or nutrients. Results of our research suggest the following genes should be tested: serotoninergic, dopaminergic (DRD2, DAT, DBH), glucocorticoid, GABAergic (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor, Monamine B, CNR1, Myo6, CRF-1 and CRF-2 receptors, and neuropeptide Y (NPY). Treatment in part should be developed that would up-regulate the expression of these genes to bring about a feeling of well being as well as a reduction in the frequency and intensity of the symptoms of PTSD.

Use of Antiepileptic Drugs for Hyperkinetic Movement Disorders by A. Siniscalchi, L. Gallelli, G. De Sarro (359-366).
Many studies investigated the use of antiepileptic drugs (AEDs) in several neurological diseases other than epilepsy. These neurological disorders, usually, involve neuronal excitability through the modulating of ion channels, receptors and intracellular signaling pathways, and are the targets of the AEDs. This article provides a review of the clinical efficacy of both conventional and newer AEDs in hyperkinetic movement disorders. Some of these indications for AEDs have been established, while others are under investigation. The modulation of GABAergic transmission may explain the neuronal hyper-excitability that underlies some forms of hyperkinetic movement disorders. So, AEDs able to increase GABAergic neurotransmission may play a role in hyperkinetic movement disorders treatment. Therefore, AEDs could represent a useful therapeutic option in the management of hyperkinetic movement disorders where the available treatments are ineffective.

The Neuropharmacology of Implicit Learning by Julia Udden, Vasiliki Folia, Karl Magnus Petersson (367-381).
Two decades of pharmacologic research on the human capacity to implicitly acquire knowledge as well as cognitive skills and procedures have yielded surprisingly few conclusive insights. We review the empirical literature of the neuropharmacology of implicit learning. We evaluate the findings in the context of relevant computational models related to neurotransmittors such as dopamine, serotonin, acetylcholine and noradrenalin. These include models for reinforcement learning, sequence production, and categorization. We conclude, based on the reviewed literature, that one can predict improved implicit acquisition by moderately elevated dopamine levels and impaired implicit acquisition by moderately decreased dopamine levels. These effects are most prominent in the dorsal striatum. This is supported by a range of behavioral tasks in the empirical literature. Similar predictions can be made for serotonin, although there is yet a lack of support in the literature for serotonin involvement in classical implicit learning tasks. There is currently a lack of evidence for a role of the noradrenergic and cholinergic systems in implicit and related forms of learning. GABA modulators, including benzodiazepines, seem to affect implicit learning in a complex manner and further research is needed. Finally, we identify allosteric AMPA receptors modulators as a potentially interesting target for future investigation of the neuropharmacology of procedural and implicit learning.

Gene Expression Profiling in Rodent Models for Schizophrenia by Jessica E. Van Schijndel, Gerard J.M. Martens (382-393).
The complex neurodevelopmental disorder schizophrenia is thought to be induced by an interaction between predisposing genes and environmental stressors. In order to get a better insight into the aetiology of this complex disorder, animal models have been developed. In this review, we summarize mRNA expression profiling studies on neurodevelopmental, pharmacological and genetic animal models for schizophrenia. We discuss parallels and contradictions among these studies, and propose strategies for future research.

Glutamatergic Targets for Enhancing Extinction Learning in Drug Addiction by R. M. Cleva, J. T. Gass, J. J. Widholm, M. F. Olive (394-408).
The persistence of the motivational salience of drug-related environmental cues and contexts is one of the most problematic obstacles to successful treatment of drug addiction. Behavioral approaches to extinguishing the salience of drug-associated cues, such as cue exposure therapy, have generally produced disappointing results which have been attributed to, among other things, the context specificity of extinction and inadequate consolidation of extinction learning. Extinction of any behavior or conditioned response is a process of new and active learning, and increasing evidence suggests that glutamatergic neurotransmission, a key component of the neural plasticity that underlies normal learning and memory, is also involved in extinction learning. This review will summarize findings from both animal and human studies that suggest that pharmacological enhancement of glutamatergic neurotransmission facilitates extinction learning in the context of drug addiction. Pharmacological agents that have shown potential efficacy include NMDA partial agonists, mGluR5 receptor positive allosteric modulators, inhibitors of the GlyT1 glycine transporter, AMPA receptor potentiators, and activators of the cystine-glutamate exchanger. These classes of cognition-enhancing compounds could potentially serve as novel pharmacological adjuncts to cue exposure therapy to increase success rates in attenuating cue-induced drug craving and relapse.

“Epileptic Encephalopathy” of Infancy and Childhood: Electro-Clinical Pictures and Recent Understandings by Pasquale Parisi, Alberto Spalice, Francesco Nicita, Laura Papetti, Fabiana Ursitti, Alberto Verrotti, Paola Iannetti, Maria Pia Villa (409-421).
There is growing interest in the diagnosis of cognitive impairment among children with epilepsy. It is well known that status of seizures control has to be carefully investigated because it can be sufficient and#x201C;per seand#x201D; to cause progressive mental deterioration conditions. Subclinical electroencephalographic discharges may have subtle effects on cognition, learning and sleep patterns, even in the absence of clinical or sub-clinical seizures. In this respect, electroencephalographic monitoring (long-term and nocturnal recording) and in particular an all night video-polysomnography (V-NPSG) record can be crucial to detect the presence of unrecognized seizures and/or an inter-ictal nocturnal EEG discharge increasing. Epileptic encephalopathies (EE) are a group of conditions in which the higher cognitive functions are deteriorate as a consequence of epileptic activity, which, in fact, consists of frequent seizures and/or florid and prolonged interictal paroxysmal discharges, focal or generalized. AEDs represent the first line in opposing the burden of both, the poor seizures control and the poor interictal discharges control, in the cognitive deterioration of EE affected children. Thus, to improve the long-term cognitive/behavioural prognosis in these refractory epileptic children, it should be taken into account both a good seizures control and a strict sleep control, choosing carefully antiepileptic drugs which are able to control not only seizures clinically recognizable but even the EEG discharges onset and its increasing and spreading during sleep. Here, we review the efficacy and safety of the newer AEDs that, to date, are used in the treatment of EE in infancy and childhood.

An Update on GABAρ Receptors by Gustavo Martinez-Delgado, Argel Estrada-Mondragon, Ricardo Miledi, Ataulfo Martinez-Torres (422-433).
The present review discusses the functional and molecular diversity of GABAand#x3c1; receptors. These receptors were originally described in the mammalian retina, and their functional role in the visual pathway has been recently elucidated; however new studies on their distribution in the brain and spinal cord have revealed that they are more spread than originally thought, and thus it will be important to determine their physiological contribution to the GABAergic trans- mission in other areas of the central nervous system. In addition, molecular modeling has revealed peculiar traits of these receptors that have impacted on the interpretations of the latest pharmacolgical and biophysical findings. Finally, sequencing of several vertebrate genomes has permitted a comparative analysis of the organization of the GABAand#x3c1; genes.