Current Neuropharmacology (v.11, #3)

Neurobiological Consequences of Sleep Deprivation by Karim Alkadhi, Munder Zagaar, Ibrahim Alhaider, Samina Salim, Abdulaziz Aleisa (231-249).
Although the physiological function of sleep is not completely understood, it is well documented that itcontributes significantly to the process of learning and memory. Ample evidence suggests that adequate sleep is essentialfor fostering connections among neuronal networks for memory consolidation in the hippocampus. Sleep deprivationstudies are extremely valuable in understanding why we sleep and what are the consequences of sleep loss. Experimentalsleep deprivation in animals allows us to gain insight into the mechanism of sleep at levels not possible to study in humansubjects. Many useful approaches have been utilized to evaluate the effect of sleep loss on cognitive function, each withrelative advantages and disadvantages. In this review we discuss sleep and the detrimental effects of sleep deprivationmostly in experimental animals. The negative effects of sleep deprivation on various aspects of brain function includinglearning and memory, synaptic plasticity and the state of cognition-related signaling molecules are discussed.

NMDA Receptors in Glial Cells: Pending Questions by David Dzamba, Pavel Honsa, Miroslava Anderova (250-262).
Glutamate receptors of the N-methyl-D-aspartate (NMDA) type are involved in many cognitive processes,including behavior, learning and synaptic plasticity. For a long time NMDA receptors were thought to be the privilegeddomain of neurons; however, discoveries of the last 25 years have demonstrated their active role in glial cells as well.Despite the large number of studies in the field, there are many unresolved questions connected with NMDA receptors inglia that are still a matter of debate. The main objective of this review is to shed light on these controversies bysummarizing results from all relevant works concerning astrocytes, oligodendrocytes and polydendrocytes (also known asNG2 glial cells) in experimental animals, further extended by studies performed on human glia. The results are dividedaccording to the study approach to enable a better comparison of how findings obtained at the mRNA level correspondwith protein expression or functionality. Furthermore, special attention is focused on the NMDA receptor subunits presentin the particular glial cell types, which give them special characteristics different from those of neurons &#150; for example, theabsence of Mg<sup>2+</sup> block and decreased Ca<sup>2+</sup> permeability. Since glial cells are implicated in important physiological andpathophysiological roles in the central nervous system (CNS), the last part of this review provides an overview of glialNMDA receptors with respect to ischemic brain injury.

Cannabinoids, Neurogenesis and Antidepressant Drugs: Is there a Link? by Manoela Viar Fogaca, Ismael Galve-Roperh, Francisco Silveira Guimaraes, Alline Cristina Campos (263-275).
Similar to clinically used antidepressants, cannabinoids can also regulate anxiety and depressive symptoms.Although the mechanisms of these effects are not completely understood, recent evidence suggests that changes inendocannabinoid system could be involved in some actions of antidepressants. Chronic antidepressant treatment modifiesthe expression of CB<sub>1</sub> receptors and endocannabinoid (EC) content in brain regions related to mood and anxiety control.Moreover, both antidepressant and cannabinoids activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase(PI3-K)&#47;Akt or PKB signaling, intracellular pathways that regulate cell proliferation and neural cell survival.Facilitation of hippocampal neurogenesis is proposed as a common effect of chronic antidepressant treatment. Genetic orpharmacological manipulations of cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>) or enzymes responsible for endocannabinoidmetabolismhave also been shown to control proliferation and neurogenesis in the hippocampus. In the present paper wereviewed the studies that have investigated the potential contribution of cannabinoids and neurogenesisto antidepressanteffects. Considering the widespread brain distribution of the EC system, a better understanding of this possible interactioncould contribute to the development of therapeutic alternatives to mood and anxiety disorders.

It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca<sup>2+</sup> inneurons. Also, some of them as L-type channels are essential for Ca<sup>2+</sup>-dependent regulation of prosurvival gene-programs.However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative andneurovascular diseases. In the present review, we explore several mechanisms by which the &#8220;harmless&#8221; VGCCs maybecome &#8220;toxic&#8221; for neurons. These mechanisms could explain how, though usually required for neuronal survival,VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca<sup>2+</sup> when: a)their density or activity increases because of aging, chronic hypoxia or exposure to &#946;-amyloid peptides or b) Ca<sup>2+</sup>-dependent action potentials carry high Ca<sup>2+</sup> loads in pacemaker neurons. Besides, we will examine conditions in whichVGCCs promote neuronal cell death without carrying excess Ca<sup>2+</sup>. This can happen, for instance, when they carry metalions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca<sup>2+</sup>-dependent prosurvivalgene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part toneurodegeneration like those of the neurovascular unit or of microglia.

Nicotinic Receptors in Neurodegeneration by Inmaculada Posadas, Beatriz Lopez-Hernandez, Valentin Cena (298-314).
Many studies have focused on expanding our knowledge of the structure and diversity of peripheral and centralnicotinic receptors. Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentamericligand-gated ion channels, which include GABA (A and C), serotonin, and glycine receptors. Currently, 9 alpha (&#945;2-&#945;10)and 3 beta (&#946;2-&#946;4) subunits have been identified in the central nervous system (CNS), and these subunits assemble to forma variety of functional nAChRs. The pentameric combination of several alpha and beta subunits leads to a great number ofnicotinic receptors that vary in their properties, including their sensitivity to nicotine, permeability to calcium andpropensity to desensitize.In the CNS, nAChRs play crucial roles in modulating presynaptic, postsynaptic, and extrasynaptic signaling, and havebeen found to be involved in a complex range of CNS disorders including Alzheimer's disease (AD), Parkinson's disease(PD), schizophrenia, Tourette's syndrome, anxiety, depression and epilepsy. Therefore, there is growing interest in thedevelopment of drugs that modulate nAChR functions with optimal benefits and minimal adverse effects. The presentreview describes the main characteristics of nAChRs in the CNS and focuses on the various compounds that have beentested and are currently in phase I and phase II trials for the treatment of neurodegenerative diseases including PD, ADand age-associated memory and mild cognitive impairment.

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology by Mirjana B. Colovic, Danijela Z. Krstic, Tamara D. Lazarevic-Pasti, Aleksandra M. Bondzic, Vesna M. Vasic (315-335).
Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of theneurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. Theenzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic andmuscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with theenzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicologyand pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversibleinhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currentlyapproved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxiccarbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced byorganophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects aredescribed, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacologicaltreatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibitedenzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticidescan be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system.Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphatesdetoxification is their degradation by corresponding phosphotriesterases.