CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 12, Issue 5, 2013

An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dosedependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess ontarget activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.

There is no sense organ specifically dedicated to time perception, as there is for other senses such as hearing and vision. However, this subjective sense of time is fundamental to our conception of reality and it creates the temporal course of events in our lives. Here, we explored neurobiological relations from the clinical perspective, examining timing ability in patients with different neurological and psychiatric conditions (e.g. Parkinson’s disease, depression, bipolar disorder, anxiety disorders and schizophrenia). The neural bases of present distortions in time perception and temporal information processing still remain poorly understood. We reviewed: a) how the brain is capable of encoding time in different environments and multiple tasks, b) different models of interval timing, c) brain structures and neurotransmitters associated with time perception, d) the relationship between memory and time perception, e) neural mechanisms underlying different theories in neural and mental processes, and f) the relationship between different mental diseases and time perception. Bibliographic research was conducted based on publications over the past thirteen years written in English in the databases Scielo, Pubmed/MEDLINE, ISI Web of Knowledge. The time perceptions research are executed to evaluate time perception in mental diseases and can provide evidence for future clinical applications.

Ischemic acute kidney injury (AKI) is usually accompanied by neuroinflammation-induced encephalopathy. However, the specific mechanism remains unclear. Toll-like receptors (TLR), specifically TLR-4 has been linked to ischemic reperfusion injury in different organs like kidney, brain and liver. Here, we induced an ischemic reperfusion kidney injury in Sprague Dawley rats. All animals were evaluated using behavioral tests which revealed locomotor activity and motor disturbances in the AKI group. The brains were then examined by immunostaining with ionized calcium binding adaptor molecule 1 (microglial marker) and TLR-4 antibodies. The histological analysis revealed significant up-regulation of TLR-4 in the hippocampus and striatum in the AKI group. These data demonstrate for the first time, the triggering effect of TLR-4 on AKI-induced neuroinflammation in the brain that may lead to AKI-induced encephalopathy. This would also generate a novel hypothesis that using TLR blockers may have a role in preventing AKI effects on the brain.

There is an enormous demand for new therapeutic interventions for a range of major disorders. The majority of clinical trials in recent years have been unsuccessful despite highly promising preclinical data. Therefore, an urgent issue confronting both the academic and commercial medical research sectors is how to optimize translation of preclinical studies. The vast majority of preclinical studies are currently performed using laboratory mice and rats. We will discuss the various opportunities for optimization of animal models of CNS disorders. One limitation of current approaches is that most studies are conducted on sedentary, unstimulated animals with unlimited access to food in the home cage, thus leading to metabolic and physiological compromise. Environmental enrichment, which enhances sensory stimulation, cognitive activity and physical exercise, has been demonstrated to induce dramatic effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. Environmental enrichment also exerts beneficial effects outside the CNS, such as a reduction in excess body fat. We propose that therapeutic interventions which are found to show promise in standard-housed preclinical models should be subsequently tested under conditions of greater environmental enrichment to identify therapeutics which continue to show efficacy in housing contexts of superior ‘environmental construct validity’. Other possible approaches to optimize the quality, validity and reporting of preclinical studies in animal models are also discussed.

Alzheimer’s disease (AD) is characterized by three major histopathological hallmarks: β-amyloid deposits, neurofibrillary tangles and gliosis. While neglected for decades, the neuroinflammatory processes coordinated by microglia are now accepted as etiologic events in AD evolution. Microglial cells are found in close vicinity to amyloid plaques and display various activation phenotypes determined by the expression of a wide range of cytokines, chemokines, and innate immune surface receptors. During the development of AD pathology, microglia fail to restrict amyloid plaques and may contribute to neurotoxicity and cognitive deficit. Nevertheless, under specific activation states, microglia can participate in cerebral amyloid clearance. This review focuses on the complex relationship between microglia and Aβ pathology, and highlights both deleterious and beneficial roles of microglial activation states in the context of AD. A deeper understanding of microglial biology will hopefully pave the way for next-generation AD therapeutic approaches aimed at harnessing these enigmatic innate immune cells of the central nervous system.

Glial cells not only serve supportive and nutritive roles for neurons, but also respond to protracted stress and insults by up-regulating inflammatory processes. The complexity of studying glial activation in vivo has led to the widespread adoption of in vitro approaches, for example the use of the bacterial toxin lipopolysaccharide (LPS, a ligand for toll-like receptor 4 (TLR4)) as an experimental model of glial activation. Astrocyte cultures frequently contain minor numbers of microglia, which can complicate interpretation of responses. In the present study, enriched (≤5% microglia) astrocytes cultured from neonatal rat cortex and spinal cord were treated with the lysosomotropic agent L-leucyl-L-leucine methyl ester to eliminate residual microglia, as confirmed by loss of microglia-specific marker genes. L-Leucyl-L-leucine methyl ester treatment led to a loss of LPS responsiveness, in terms of nitric oxide and cytokine gene up-regulation and mediator (pro-inflammatory cytokines, nitric oxide) output into the culture medium. Surprisingly, when astrocyte/microglia co-cultures were then reconstituted by adding defined numbers of purified microglia to microgliadepleted astrocytes, the LPS-induced up-regulation of pro-inflammatory gene and mediator output far exceeded that observed from cultures containing the same numbers of microglia only. Similar behaviors were found when examining interleukin-1β release caused by activation of the purinergic P2X7 receptor. Given that astrocytes greatly outnumber microglia in the central nervous system, these data suggest that a similar interaction between microglia and astrocytes in vivo may be an important element in the evolution of an inflammatory pathology.

Schizophrenia affects approximately 1% of the world population, and the majority of pharmacologically based treatments for this disorder are ligands that interact with monoaminergic transmission. However, there is a wealth of evidence that various neuropeptides are often co-released with monoamine neurotransmitters, and that ligands acting at neuropeptide receptors modulate monoaminergic transmission as well as schizophrenia-related behaviors in preclinical animal models. Such neuropeptide systems include neurotensin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, oxytocin, opioid peptides, tachykinins, thyrotropin-releasing hormone, and orexins. The purpose of this review will be to summarize the existing preclinical and clinical literature on the role of various neuropeptide systems as modulators of schizophrenia-related behaviors, and the potential of targeting these systems for the development of novel antipsychotic medications.

Drug addiction is a chronic neuropsychiatric disorder which is characterized by a compulsion to take drugs and loss of control in limiting intake. The worldwide impact of drug addiction on morbidity and mortality is very high. Evidence from preclinical and clinical studies suggests that brain nicotinic acetylcholine receptors (nAChRs), play a critical role in various addictive disorders, including nicotine addiction and alcoholism. Thus, there is an increasing impetus in developing new therapeutics for addictive disorders by targeting brain nAChRs. This review highlights the important preclinical findings involving nAChR ligands in regulating nicotine, alcohol and other addictive drug-induced neurobiological changes in animal models and humans. A number of partial agonists or antagonists targeting nAChRs have shown therapeutic benefit in nicotine addiction and alcohol use disorders are also discussed. Furthermore, the role of nAChRs in other addictive disorders is reviewed. Overall, novel pharmacological agents that target brain nAChRs for future drug development are discussed.

Coenzyme Q10 (CoQ10) is critical for the cell power supply in mitochondria. CoQ10 shuttles electrons from complexes I and II to complex III, and can be anti-oxdiative. Neurons require high energy for synaptic transmission and therefore the mitochondria dysfunction often leads to severe neuronal degeneration, as observed in many neurological disorders. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Alzheimer's disease, Parkinson’s disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, Huntington’s disease and amyotrophic lateral sclerosis. Here we discuss a large number of preclinical and clinical trials for CoQ10 to elucidate the mechanisms underlying CoQ10 therapy. The rational applications as a therapeutic agent in neurological disorders are discussed.

Hipericum perforatum is a well-known herbal for its antidepressant property. Recently, it has been shown to have nootropic effects against neurodegenerative disorders. The aim of the present study was to evaluate the protective role of chronic administration of two standardized extract of Hypericum perforatum SHP1 rich in hyperforin (6 %) and SHP2 extract poor in hyperforin (0.2 %) on the neurodegeneration induced by chronic administration of rotenone in rats. Quercetin in liposomes, one active constituent, was tested in the same experimental conditions. The animals received pretreatments with SHP1 (4 mg/Kg, ip), SHP2 (4 mg/Kg, ip) or quercetin liposomes (25 and 100 mg/kg, ip) 60 min before of rotenone injection (2.5 mg/kg) for 45 days. Pretreatment of the animals with SHP1 and SHP2 efficiently halted deleterious toxic effects of rotenone, revealing normalization of catalepsy in addition to amelioration of neurochemical parameters. Also, SHP1 reduced neuronal damage, diminishing substantia nigra dopaminergic cell death caused by the pesticide, indicating benefit of neuroprotective therapy. In general, the SHP1 was more active than SHP2. In addition, SHP1 inhibited the apoptotic cascade by decreasing Bax levels. The results presented here indicate that mainly hyperforin and quercetin, may be involved in the neuroprotective action of Hypericum standardized extracts. Combination of dietary antioxidants could provide better therapeutic advantage for the management of Parkinson, and possibly other neurodegenerative disorders. Therefore H. perforatum standardized extract enriched in hyperforin, could be a better alternative for depressed elderly patients with degenerative disorders exhibiting elevated oxidative stress status.

Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed a crucial role of neuroinflammation that is initiated and driven by activated microglial cells and their neurotoxic products during PD pathogenesis. Inflammatory responses manifested by glial reactions are currently recognized as one of the prominent features of PD. Indeed, activated microglial cells have been detected in the SNpc of patients with PD. Postmortem analysis and preclinical investigations conducted in various animal models exposed to neurotoxins have also revealed dramatic and massive astrogliosis with the presence of activated microglial cells in the SNpc. Although a number of neurotoxic, pharmacologic, and transgenic animal models are available for mechanistic and drug discovery studies in PD, selection and use of a good experimental PD model has always been a challenge. Significant advances in modeling neuroinflammatory features and expansion to new species have occurred to better characterize the pathological mechanisms in PD. Here, we outline the remarkable array of animal and cellular neuroinflammatory models available, with particular emphasis on their benefits and pitfalls and the contribution each has made to delineate the neuroinflammatory mechanisms underlying PD. This review suggests that further investigation concerning use of optimal neuroinflammatory experimental PD models might help to identify disease-modifying therapeutic approaches in future drug discovery and may shed light on understanding PD pathogenesis.

Stroke is the second leading cause of death, after ischemic heart disease, and accounts for 9% of deaths worldwide. According to the World Health Organization [WHO], 15 million people suffer stroke worldwide each year. Of these, more than 6 million die and another 5 million are permanently disabled. Reactive oxygen species [ROS] have been implicated in brain injury after ischemic stroke. There is evidence that a rapid increase in the production of ROS immediately after acute ischemic stroke rapidly overwhelm antioxidant defences, causing further tissue damage. These ROS can damage cellular macromolecules leading to autophagy, apoptosis, and necrosis. Moreover, the rapid restoration of blood flow increases the level of tissue oxygenation and accountsfor a second burst of ROS generation, which leads to reperfusion injury. Current measures to protect the brain against severe stroke damage are insufficient. Thus, it is critical to investigate antioxidant strategies that lead to the diminution of oxidative injury. The antioxidant vitamins C and E, the polyphenol resveratrol, the xanthine oxidase [XO] inhibitor allopurinol, and other antioxidant strategies have been reviewed in the setting of strokes. This review focuses on the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of ischemic stroke, and the novel therapeutic strategies to be tested to reduce the cerebral damage related to both ischemia and reperfusion.