Current Neuropharmacology (v.12, #1)

Preface: by Tom Salt (1-1).

Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimerµs Disease by Angel Agis-Torres, Monica Sollhuber, Maria Fernandez, J.M. Sanchez-Montero (2-36).
The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growingamount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD isthe most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, whichcontrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or evenunknown. This review offers a view of the current state of knowledge about AD which includes more relevant findingsand processes that take part in the disease; it also shows more relevant past, present and future research on therapeuticdrugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigmwill lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD butalso in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targetsthat should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goesfrom the pathology and the processes involved in AD to the strategies to consider in on-going and future researches.

Purinergic Signaling and Hippocampal Long-Term Potentiation by Robert Duster, Jos Prickaerts, Arjan Blokland (37-43).
The purines ATP and adenosine are widely recognized for their neuromodulatory effects. They have beenshown to have effects on neurons via various receptors and interactions with glial cells. In particular, long-termpotentiation (LTP) in hippocampal slice preparations has been found to be modulated by ATP and adenosine. This reviewgives an overview of purinergic signaling in relation to hippocampal LTP and memory formation. The data supports thehypothesis that adenosine mediates a tonic suppression of synaptic transmission. Thus, low adenosine levels appear toincrease basal synaptic activity via a decreased activation of the inhibitor A1 receptor, consequently making it moredifficult to induce LTP because of lower contrast. During high stimulation, the inhibition of neighboring pathways byadenosine, in combination with an A2a receptor activation, appears to increase contrast of excited pathways against a nonexcitedbackground. This would enable amplification of specific signaling while suppressing non-specific events.Although a clear role for purinergic signaling in LTP is evident, more studies are needed to scrutinize the modulatory roleof ATP and adenosine and their receptors in synaptic plasticity and memory.

Pregabalin in Neuropathic Pain: Evidences and Possible Mechanisms by Vivek Verma, Nirmal Singh, Amteshwar Singh Jaggi (44-56).
Pregabalin is an antagonist of voltage gated Ca2+ channels and specifically binds to alpha-2-delta subunit toproduce antiepileptic and analgesic actions. It successfully alleviates the symptoms of various types of neuropathic painand presents itself as a first line therapeutic agent with remarkable safety and efficacy. Preclinical studies in variousanimal models of neuropathic pain have shown its effectiveness in treating the symptoms like allodynia and hyperalgesia.Clinical studies in different age groups and in different types of neuropathic pain (peripheral diabetic neuropathy,fibromyalgia, post-herpetic neuralgia, cancer chemotherapy-induced neuropathic pain) have projected it as the mosteffective agent either as monotherapy or in combined regimens in terms of cost effectiveness, tolerability and overallimprovement in neuropathic pain states. Preclinical studies employing pregabalin in different neuropathic pain modelshave explored various molecular targets and the signaling systems including Ca2+ channel-mediated neurotransmitterrelease, activation of excitatory amino acid transporters (EAATs), potassium channels and inhibition of pathwaysinvolving inflammatory mediators. The present review summarizes the important aspects of pregabalin as analgesic inpreclinical and clinical studies as well as focuses on the possible mechanisms.

Major depressive disorder (MDD) is a serious mental disorder that ranks among the major causes of diseaseburden. Standard medical treatment targeting cerebral monoamines often provides only insufficient symptom relief andfails in approximately every fifth patient. The complexity of MDD therefore, reflects more than monoaminergicdysregulation. Initial research argues the case for excessive glutamate levels, suggesting that antiglutamatergic drugsmight be useful in treating MDD. Ketamine is a non-selective, high-affinity N-methyl-D-aspartate receptor (NMDAR)antagonist most commonly used in pediatric and animal surgery. In the past, ketamine has gained popularity because of itsability to rapidly elevate mood, even in treatment-resistant and bipolar depression. However, there are still many obstaclesbefore widespread clinical approval of ketamine treatment could become reality. In this review, ketamine's powerfulantidepressant effects are discussed and further research necessary for therapeutic application is outlined. NMDARantagonists provide an entirely new way of treating the manifold appearances of depression that should not be left unused.

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhoodneurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of thesynapse with alterations in different forms of synaptic communication and neuronal network connectivity. The majorexcitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synapticplasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors inASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are alsoaltered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidencethat ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellularand functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the contextof ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments forthe core symptoms of ASD and FXS.