Current Neuropharmacology (v.12, #3)

Protein Kinase C-Related Kinase (PKN/PRK). Potential Key-Role for PKN1 in Protection of Hypoxic Neurons by Bettina Thauerer, Stephanie zur Nedden, Gabriele Baier-Bitterlich (213-218).
Serine/threonine protein kinase C-related kinase (PKN/PRK) is a family of three isoenzymes (PKN1, PKN2,PKN3), which are widely distributed in eukaryotic organisms and share the same overall domain structure. The Nterminalregion encompasses a conserved repeated domain, termed HR1a-c as well as a HR2/C2 domain. Theserine/threonine kinase domain is found in the C-terminal region of the protein and shows high sequence homology toother members of the PKC superfamily.;In neurons, PKN1 is the most abundant isoform and has been implicated in a variety of functions including cytoskeletalorganization and neuronal differentiation and its deregulation may contribute to neuropathological processes such asamyotrophic lateral sclerosis and Alzheimer's disease. We have recently identified a candidate role of PKN1 in theregulation of neuroprotective processes during hypoxic stress. Our key findings were that: 1) the activity of PKN1 wassignificantly increased by hypoxia (1% O2) and neurotrophins (nerve growth factor and purine nucleosides); 2) Neuronalcells, deficient of PKN1 showed a decrease of cell viability and neurite formation along with a disturbance of the F-actinassociatedcytoskeleton; 3) Purine nucleoside-mediated neuroprotection during hypoxia was severely hampered in PKN1deficient neuronal cells, altogether suggesting a potentially critical role of PKN1 in neuroprotective processes.;This review gives an up-to-date overview of the PKN family with a special focus on the neuroprotective role of PKN1 inhypoxia.

The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment by Felice Iasevoli, Carmine Tomasetti, Elisabetta F. Buonaguro, Andrea de Bartolomeis (219-238).
Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked itspathophysiology to postsynaptic abnormalities.;The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia.More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic andmetabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Beingimplicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSDconstitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggeststhat some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, includingschizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights forthe development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects ofcurrent schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against thisdevastating illness.;The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophreniapathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynapticmolecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, thepossibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will bediscussed.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far,the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate thepathophysiology of AD, the disease is still incurable.;The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of A?,hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction and deterioration ofsynaptic transmission. These factors together, accentuate changes in the CNS homeostasis, starting a complex process ofinterconnected physiological damage, leading to cognitive and memory impairment and neuronal death.;A recent approach for the rational design of new drug candidates, also called multitarget-directed ligand (MTDL)approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compoundsacting simultaneously on diverse biological targets. This review aims to show some recent advances and examples of theexploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Background: Dimethyl fumarate (BG-12, Tecfidera®) is a new oral drug approved by FDA and EMA in March2013 for relapsing - remitting multiple sclerosis (RRMS). The drug was much anticipated because of its possiblesuperiority over currently available medications: fingolimod and teriflunomide as the only MS treatments currentlyavailable in oral form.;Objective: The aim of this systematic review with meta-analysis was to assess the efficacy and safety of BG-12 in thetreatment of RRMS.;Methods: A systematic literature search was conducted in Medline/PubMed, EMBASE, and Cochrane Library up till 3rdNovember, 2013. We sought all published randomized clinical trials evaluating the use of dimethyl fumarate for thetreatment of patients with RRMS. All included studies were critically appraised and analyzed with the use of ReviewManager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) statement protocol.;Results: Two trials, DEFINE and CONFIRM involved 2 651 patients and compared dimethyl fumarate taken either two orthree times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients receivedglatiramer acetate. The overall results of the meta-analysis showed that BG-12 (at both dosages) given to patients withRRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who hada relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years.The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be moreeffective in the treatment of RRMS.;Conclusions: Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinicaldisease parameters and other measures of disease activity in RRMS. The safety profile of the study agent was acceptable.

Potential Effects of Cannabidiol as a Wake-Promoting Agent by Eric Murillo-Rodriguez, Andrea Sarro-Ramirez, Daniel Sanchez, Stephanie Mijangos-Moreno, Alma Tejeda-Padron, Alwin Poot-Ake, Khalil Guzman, Elda Pacheco-Pantoja, Oscar Arias-Carrion (269-272).
Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased.Most attention has focused on Δ9-tetrahydrocannabinol (Δ9-THC) as it is the psychoactive constituent of Cannabis sativa(C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropicproperties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacologicalproperties of CBD with significant findings; furthermore, this compound has raised promising pharmacological propertiesas a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role ofCBD as a wake-inducing drug.

Evidence for an Immune Role on Cognition in Schizophrenia: A Systematic Review by Rafael Ribeiro-Santos, Antonio Lucio Teixeira, Joao Vinicius Salgado (273-280).
Objective: Recent evidence has associated immune and inflammatory changes to cognitive performance inmany diseases, including schizophrenia. Since this is a new research field where concepts are not yet solid and newquestions and hypothesis are still arising, the present study aimed at summarizing the available clinical data associatingschizophrenia, cognition and inflammation/immune function.;Methods: A systematic review of the literature was made by searching the following terms in Medline: “schizophrenia orpsychosis or psychotic” AND “inflamm* or immun* or cytokine or IL-* or TNF-* or kynureni* or KYNA”, AND“cognit* or attention or memory or executive function”.;Results: Seventy five papers were identified using the selected terms, and seven papers were included in the review.Papers excluded focused mainly on basic research or other neuropsychiatric disorders.;Conclusions: Recent findings link inflammatory markers to cognition in schizophrenia, suggesting that inflammation isassociated with worst cognitive performance. Microglial activation, monoaminergic imbalance, brain abnormalities andthe kynurenine pathway are possible mechanisms underlying cognitive impairment in schizophrenia. Clinical trials withaddition of immunomodulatory drugs have shown promising results, opening new windows to tackle cognition inschizophrenia.

Effects of the KIBRA Single Nucleotide Polymorphism on Synaptic Plasticity and Memory: A Review of the Literature by Laetitia C. Schwab, Vincent Luo, Chelsey L. Clarke, Pradeep J. Nathan (281-288).
There has been a great deal of interest recently in genetic effects on neurocognitive performance in the healthypopulation. KIBRA -a postsynaptic protein from the WWC family of proteins- was identified in 2003 in the human brainand kidney and has recently been associated with memory performance and synaptic plasticity. Through genome-widescreening, a single nucleotide polymorphism (SNP) was detected in the ninth intron of KIBRA gene (T? C substitution)and was implicated in human memory and the underlying neuronal circuitry. This review presents a synopsis of thecurrent findings on the effects of the KIBRA SNP on human memory and synaptic plasticity. Overall the findings suggestimpaired memory performance and less efficient or impaired hippocampal/medial temporal lobe (MTL) activation in CChomozygotes (in comparison to T carriers) with some differences between young and older subjects. This review alsohighlights limitations and potential sources for variability of studies' imaging findings along with future perspectives andimplications for the role of KIBRA in memory-related brain systems.

Herbal Insomnia Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence by Yuan Shi, Jing-Wen Dong, Jiang-He Zhao, Li-Na Tang, Jian-Jun Zhang (289-302).
Insomnia is a common sleep disorder which is prevalent in women and the elderly. Current insomnia drugsmainly target the γ-aminobutyric acid (GABA) receptor, melatonin receptor, histamine receptor, orexin, and serotoninreceptor. GABAA receptor modulators are ordinarily used to manage insomnia, but they are known to affect sleepmaintenance, including residual effects, tolerance, and dependence. In an effort to discover new drugs that relieveinsomnia symptoms while avoiding side effects, numerous studies focusing on the neurotransmitter GABA and herbalmedicines have been conducted. Traditional herbal medicines, such as Piper methysticum and the seed of Zizyphus jujubaMill var. spinosa, have been widely reported to improve sleep and other mental disorders. These herbal medicines havebeen applied for many years in folk medicine, and extracts of these medicines have been used to study theirpharmacological actions and mechanisms. Although effective and relatively safe, natural plant products have some sideeffects, such as hepatotoxicity and skin reactions effects of Piper methysticum. In addition, there are insufficient evidencesto certify the safety of most traditional herbal medicine. In this review, we provide an overview of the current state ofknowledge regarding a variety of natural plant products that are commonly used to treat insomnia to facilitate futurestudies.