Mini Reviews in Medicinal Chemistry - Volume 11, Issue 7, 2011

In recent years the conception that neuroinflammation plays a pivotal role in the pathogenesis of a number of neurodegenerative diseases has been extended to even archetypal endogenous psychoses, namely mood disorder and schizophrenia. The neuroinflammation associated with these neuropsychiatric diseases is revealed by increased levels of inflammatory mediators, including cytokines, in the peripheral blood and by abnormal glial activation in the diseased CNS. Accumulating evidence indicates that psychopharmaceuticals such as the antidepressants, antipsychotics and cannabinoids have potency to attenuate neuroinflammation. Accordingly, the efficacy of these psychotropics may be partially attributable to suppression of neuroinflammation. In fact, agents that possess anti-inflammatory properties such as the cyclooxygenase-2 inhibitor celecoxib [1] and omega-3 fatty acids [2] have been reported to have beneficial effects in mood disorder and schizophrenia. This mini-hot topic issue has collected 4 expert mini-reviews on this theme. Both in vivo and in vitro studies have shown that antidepressants possess anti-neuroinflammatory properties, inhibiting inflammatory mediator expression and the pathological activation of glial cells. The first review gives a brief description of the term neuroinflammation and provides an overview of those studies. It also proposes possible mechanisms of the antineuroinflammatory efficacy. Antipsychotics, especially novel atypical antipsychotics, have been also documented to exert anti-neuroinflammatory effects on activated glial cells. The second article by Kato et al. presents data on the effects of various types of antipsychotics on glial activation and speculates that the anti-neuroinflammatory mechanisms of the drugs involve effects on intracellular Ca2+ kinetics. The precise mechanisms by which certain psychopharmaceuticals exert anti-inflammatory effects still remain to be elucidated. However, recent studies have indicated that several non-conventional antidepressants [3] and antipsychotics [4] inhibit microglial activation through suppression of elevated concentrations of intracellular Ca2+. Accordingly, modulating cellular Ca2+ signaling might be a common mechanism underlying the anti-neuroinflammatory effects of antidepressants and antipsychotics. Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain [5]. A number of animal studies have shown that both antidepressants [6, 7] and atypical antipsychotics [8, 9] induce BDNF expression in the hippocampus after chronic treatment. Furthermore, a postmortem study has shown that BDNF immunoreactivity in the hippocampus from subjects treated with antidepressants is increased compared to that in the hippocampus from antidepressant-untreated subjects [10]. Another postmortem study has revealed that the mRNA expressions of BDNF and its receptor trkB tyrosine kinase are decreased in the hippocampus of individuals with mood disorders and schizophrenia, suggesting that decreased brain levels of BDNF is involved in the etiologies of these endogenous psychoses [11]. Interestingly, recent studies have established that BDNF itself has anti-neuroinflammatory effects. In the brain of mice with experimental autoimmune encephalomyelitis, BDNF gene delivery decreased the mRNA expression of the inflammatory cytokines, tumor necrosis factor (TNF)-α and interferon-γ, as well as of the inflammatory adhesion molecules, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, whereas it increased that of the anti-inflammatory cytokines, interleukin (IL)-10 and IL-11 [12]. In the rat ischemic brain induced by cerebral artery occlusion, intranasal BDNF administration downregulated TNF-α, while it upregulated IL-10 at both protein and mRNA levels [13]. In the present special issue, Mizoguchi et al. discuss the possible role of BDNF in the pathophysiology of neuropsychiatric disorders by focusing on its effect on intracellular Ca2+ signaling in microglial cells. They also give details of the mechanism by which BDNF induces sustained elevation of on intracellular Ca2+ in rodent microglia. The plant Cannabis sativa, commonly known as marijuana, has been used for medicinal purposes due to its manifold bioactivity such as sedative, analgesic and appetite-stimulating properties. In fact, it was one of the most commonly prescribed medicines in the U.S. pharmacopoeia until its criminalization in the late 1930s [14]. Cannabinoids, which include phytocannabinoids and synthetic compounds mimicking phytocannabinoid actions, have been demonstrated to exert antiinflammatory effects through the activation of cannabinoid receptor type 2. In addition, cannabinoids have been reported to possess anti-oxidant properties aside from the interaction with cannabinoid receptors. Therefore, cannabinoids appear to have a therapeutic potential against such neurodegenerative disease as Parkinson's disease (PD). However, cannabinoids could also contribute to neurotoxicity since they may impair the activity of mitochondrial enzyme and increase oxidative stress. In this special issue, Little et al. discusses the pros and cons of the cannabinoid influence on the PD pathogenesis associated with neuroinflammation. Although some psychopharmaceuticals could be useful for treatment or prevention against the various CNS pathologies associated with inflammation, further studies are clearly warranted to consolidate the evidence of their anti-neuroinflammatory properties and mechanisms. The editor would like to thank the authors for their great contribution to this special issue and the anonymous reviewers for their insightful comments. Sincere acknowledgements are also extended to Dr. Edith G. McGeer for her kind support and Ms. Sabiha Aftab for publication management....

Neuroinflammation is traditionally defined as the brain's innate immune response and is also considered to be a glial-cell propagated inflammation. Increasing evidence indicates that neuroinflammation plays an important role in some cases of major depression and also that antidepressants possess anti-neuroinflammatory properties. Inhibition of neuroinflammation may represent a novel mechanism of action of antidepressant treatment. In vivo studies with animal models of neurological conditions have shown that various types of antidepressants exert inhibitory effects on the expression of inflammatory mediators, including cytokines, as well as on both microgliosis and astrogliosis in the inflamed CNS. In vitro studies using pathologically activated rodent microglia or mixed glial cells have demonstrated that various types of antidepressants diminish glial generation of inflammatory molecules. One of the most plausible mechanisms of such anti-neuroinflammatory efficacy of the drugs, as well as their antidepressant actions, seems to involve elevated intracellular cAMP levels. But the exact mechanism has still to be elucidated.

Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the world's population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation.

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO) and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. We have recently reported that BDNF induces a sustained increase in [Ca2+]i through binding with the truncated TrkB receptor, resulting in activation of the PLC pathway and store-operated calcium entry (SOCE) in rodent microglial cells. Sustained activation of SOCE, possibly mediated by TRP channels, occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, selective serotonin reuptake inhibitors (SSRIs), including paroxetine or sertraline, potentiated the BDNFinduced increase in [Ca2+]i in rodent microglial cells This article provides a review of recent findings on the role of BDNF in the pathophysiology of neuropsychiatric disorders, especially by focusing on its effect on intracellular Ca2+ signaling in microglial cells.

The cannabinoid system is represented by two principal receptor subtypes, termed CB1 and CB2, along with several endogenous ligands. In the central nervous system it is involved in several processes. CB1 receptors are mainly expressed by neurons and their activation is primarily implicated in psychotropic and motor effects of cannabinoids. CB2 receptors are expressed by glial cells and are thought to participate in regulation of neuroimmune reactions. This review aims to highlight several reported properties of cannabinoids that could be used to inhibit the adverse neuroinflammatory processes contributing to Parkinson's disease and possibly other neurodegenerative disorders. These include anti-oxidant properties of phytocannabinoids and synthetic cannabinoids as well as hypothermic and antipyretic effects. However, cannabinoids may also trigger signaling cascades leading to impaired mitochondrial enzyme activity, reduced mitochondrial biogenesis, and increased oxidative stress, all of which could contribute to neurotoxicity. Therefore, further pharmacological studies are needed to allow rational design of new cannabinoid-based drugs lacking detrimental in vivo effects.

High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of the tropism of normal stem cells for glioma cells might be one.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Its etiology includes chronic liver disease, viral hepatitis, alcoholism, and hepatic cirrhosis. Both oxidative stress and inflammatory mechanisms have been implicated in HCC pathophysiology. Surgical resection and liver transplants are currently used to treat HCC. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. The use of dietary antioxidants and micronutrients has been proposed as a useful means for the HCC management. Trace elements such as selenium are involved in several major metabolic pathways as well as antioxidant defense systems. In particular, selenium is an important oligo-element that plays a central role in cellular redox processes even if the amount necessary for the cell functions is in a very narrow range. However, selenium is involved in the prevention of numerous chronic diseases and cancers. This review will examine the potential role of selenium in HCC prevention and treatment and, in detail, focus on: i) description of selenium in biological systems and in mammalian proteins, ii) involvement of selenium in HCC, iii) in vivo and in vitro effects of selenium in preclinical models of HCC and iv) potential challenges involved in the selenium use in the prevention and treatment of HCC.

The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi-targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy.

The electron transport chain (ETC) has become a promising pharmacological target as ETC impairment by reactive oxygen species (ROS) has been detected in several diseases. Therefore, for a better understanding of the actions of mitochondria-targeted antioxidants, it must be considered the interplay between the sources of ROS during disease, the chemical interconversions of ROS and their differential reactivity with ETC components. This review contrasts these aspects with available data about mitochondrial damage in specific diseases to give an insight into the importance of ROS chemistry in the rational use of mitochondria-targeted antioxidants, putting emphasis on the case of MitoQ.