Current Pharmaceutical Design - Volume 18, Issue 12, 2012

The modern era of the treatment of major psychotic disorders started in 1927 when Manfred Sakel introduced the insulin-coma therapy but the real revolution came in 1938, when Lucio Bini and Ugo Cerletti documented the first therapeutic use of electrically induced seizures in humans. Later, in 1952 the first antipsychotic, cholpromazine was introduced by Henry Laborit, Jean Delay and Pierre Deniker while lithium was established in the 70s thanks to the works of Mogens Schou and Christian Baastrup. In 1957 antidepressants appeared, haloperidol was introduced in the 70s and second generation antipsychotics in the 90s. Valproate and carbamazepine were established in the 80s. Thus a variety of agents and therapeutic modalities are available today for the treatment of schizophrenia, bipolar spectrum disorders and other psychotic disorders and often are used in combination to treat clusters of symptoms with little concern for the primary diagnosis. In schizophrenia, which has a year prevalence of around 1% and life prevalence 1.4% in the general population and an incidence of around 10 per 10,000 [1], the advances in treatment made possible the release of a great number of patients from asylums, and gave a chance for the deinstitutionalization movement. However, recent data suggest that major impairment is still the rule rather than the exception. On the other hand, the treatment of BD (which has a lifetime prevalence of 3-6.5% including a wider spectrum of bipolarity in comparison to the DSM-IV-TR definition [2-4]) is complex and full of caveats for the clinician. Contrary to the approach by Kraepelin, today we know that a significant proportion of bipolar patients remain symptomatic and disabled, many of them suffering from subsyndromal depression and significant disability. Schizophrenia and bipolar disorder include patient adherence, long term clinical stability and prevention, treatment of comorbid depression and suicide and eventually the psychosocial rehabilitation and restoration of functioning and the treatment of the high rates of somatic morbidity and mortality. Social stigma represents another important issue. It is clear that the outcome of available treatment and care for major psychotic illnesses is suboptimal. These unmet needs should be addressed urgently, if the next generation of treatments is going to constitute a progress for the benefit of the patients. The excitatory aminoacids system and especially the NMDA receptor has been at the focus of research especially concerning schizophrenia and the knowledge on their involvement is coming of age. Several theoretical proposals for possible therapeutic targets in this system have been developed and the first clinical data have already appeared [5, 6]. The current supplement aims to explore the possible future role of agents acting on the NMDA receptor complex. In this frame, Xenia Gonda provided a short and comprehensive description of the basic pharmacology of these receptors [7]. Martin Bauer reviewed the data concerning the prodromal phase of schizophrenia, the limitations of the dopaminergic hypothesis and the possible importance of NMDA receptors in this process [8]. Thomas Schwartz reviewed genetic data supporting the NMDA glutamate receptor hypothesis for schizophrenia [9] and Corina Bondi comments on glutamatergic animal models of schizophrenia [10] while myself reviewed the possible involvement of NMDA glutamate receptor in the etiopathogenesis of bipolar disorder and its therapeutic implications [11]

NMDA receptors are ionotropic receptors mediating glutamatergic neurotransmission and play a role in several basic functions in the central nervous system, from regulating neurodevelopment and synaptic plasticity, learning and memory formation, cognitive processes, rhythm generation necessary for locomotor activity and breathing, and excitotoxicity. Due to their complex involvement in the above processes, NMDA receptors have been established to play a role in the etiopathology of several neuropsychiatric disorders such as ischaemia and traumatic brain injury, neurodegenerative disorders, pain syndromes, addiction, affective disorders and such neurodevelopmental disorders as autism or schizophrenia. NMDA receptors contain multiple types of subunits with distinct functional and pharmacological properties making the picture more complex. These receptors also offer multiple binding sites to be targeted with pharmacons, however, early broad-spectrum NMDA receptor antagonists had limited clinical use due to their intolerable adverse effect profile. The discovery of several types of subunit selective NMDA receptor antagonists may offer valuable therapeutic possibilities for several disorders, with improved clinical efficacy and decreased side effects. However, in spite of our increasing knowledge concerning the involvement of NMDA receptors in pathological processes, molecules with a selective action, tolerable side effect profile and good clinical efficacy are still only in clinical development in the majority of cases. Nevertheless, NMDA receptors offer a novel opportunity in the treatment of various neuropsychiatric conditions.

It is known that early treatment improves the outcome in patients with schizophrenia. Treatment interventions prior to the onset of frank psychosis hold the promise of even better outcomes. Since schizophrenia typically has a year long prodromal phase before becoming clinically manifest, the field has made increasing efforts to define reliable criteria for subjects who are at high risk for psychosis (at-risk mental state, ARMS subjects). Still, no single test exists that would be sensitive and specific enough to justify individual treatment decisions in ARMS subjects. The most prominent theory on the pathogenesis of schizophrenia, the dopamine hypothesis, has undergone several modifications since its formulation more than half a century ago. Although there is nearly indisputable evidence for increased dopamine neurotransmission in schizophrenia, recent theories suggest that increased dopamine function is not causal, but can be seen as a final common pathway mediating psychosis in schizophrenia. Dopaminergic and glutamatergic neurons interact at striatal interneurons to control striatal output and information processing in fast glutamatergic networks. Both, glutamatergic and dopaminergic neurotransmission, are believed to be already altered in prodromal phases of schizophrenia.. Results from neuroimaging studies indicate that dopamine transmission is altered before the outbreak of psychosis, and recent findings also suggest alterations in dopamineglutamate coupling in ARMS subjects. Improved methods for imaging dopamine and glutamate function in the living brain have thus the potential to identify young people at ultra- high risk who would most likely benefit from early psychological and pharmacological interventions.

The Dopamine Hypothesis has been the leading theory used to explain the mechanism of the clinical manifestation of schizophrenia symptoms for decades. It is unclear if excess dopaminergic activity is the primary pathophysiology causing psychosis or if this dopamine excess is triggered by upstream, downstream or neurodevelopmental abnormalities. A corollary hypothesis suggests that the glutamatergic system may be involved in the pathogenesis of schizophrenia, and that dysfunction of the glutamate system may actually lead to dopamine excess. The NMDA Receptor Hypofunction Hypothesis suggests that malfunctioning NMDA receptors may be the cause for the theoretically hypofunctioning glutamate system. This paper seeks to describe and discuss the potential underlying genetic vulnerabilities of the NMDA receptor and how aberrant genes coding for this receptor may lead to schizophrenia symptoms.

Dysregulation of glutamate neurotransmission has been implicated in schizophrenia primarily because antagonists of the nmethyl- d-aspartate (NMDA) subtype of glutamate receptors exacerbate preexisting symptoms of schizophrenia in patients and produce behavioral disruptions that resemble some symptoms of schizophrenia in healthy individuals. Given this, NMDA receptor antagonists have been used extensively to model aspects of the disease in laboratory animals and have provided a useful preclinical tool for testing novel treatment strategies. More recent genetic and postmortem findings have implicated proteins other than the NMDA receptor in the pathophysiology of schizophrenia which play a role in regulation of the glutamate synapse. Animal models developed based on these findings have the potential of increasing our mechanistic understanding of the disease. Here we review some of the pertinent literature related to pharmacological and genetic animal models of glutamate dysfunction in schizophrenia.

Glutamate is the most abundant excitatory neurotransmitter in the brain and the ionotropic NMDA receptor is one of the major classes of its receptors, thought to play an important role in schizophrenia and mood disorders. The current systematic review summarized the evidence concerning the involvement of NMDA receptors in the pathophysiology of bipolar disorder. Genetic studies point to the genes encoding the NMDA 1, 2A and 2B subunits while neuropathological studies suggest a possible region specific decrease in the density of NMDA receptor and more consistently a reduced NMDA-mediated glutamatergic activity in patients with bipolar disorder in the frame of slower NMDA kinetics because of lower contribution of NR2A subunits. However the literature is poor and incomplete; future research is necessary to elucidate the mechanisms underlying bipolar disorder and its specific relationship to a possible NMDA malfunction and to explore the possibility of developing novel therapeutic agents.

Over recent years, neutrophil functions have extensively been reevaluted. For instance, it has been found that extracellular traps generated by activated neutrophils are able to perform a very effective antimicrobial activity against a plethora of microorganisms. In addition, neutrophils possess the ability to interact with monocytes/macrophages either via release of their granule content or via efferocytosis. Efferocytosis is based on neutrophil clearance by macrophages, which, in turn, exert pro- or antinflammatory effects. Furthermore, alarmins released by neutrophils have been shown to mobilize and activate dendritic cells as well as macrophages for antigenpresentation to occur. Finally, other researchers have demonstrated that neutrophils act as suppressor cells by deprivation of arginine in T cells. From a clinical point of view, it is well known that neutrophils are present as activated effector cells in a number of diseases such as infectious disease, sepsis, autoimmune disease, cardiovascular disease and tumors. They play pro-inflammatory and angiogenetic effects in some cases, while in other cases they depress host immune response. In this review, also emphasis will be placed on neutrophil functional deficits which seem to participate to the pathogenesis of various diseases, e.g., viral hepatitis C infection and inflammatory bowel disease. Finally, novel therapeutic measures able to modulate neutrophil functions will be described with special reference to both immune agents and natural products.

Carvedilol is a nonselective β-blocker with α1-adrenergic blocking and antioxidant properties. A number of preclinical experiments and clinical trials have demonstrated that carvedilol provides prominent benefit in heart failure. However, less research has been done in the area of animal models of viral myocarditis. This paper reviews the use of carvedilol in animal models of viral myocarditis. The experimental evidence strongly suggests that carvedilol, but not metoprolol (a selective β1-adrenergic blocking agent), protects against viral myocarditis and the superior cardioprotection effect of carvedilol to metoprolol may be due to its upregulating the production of antiinflammatory cytokines, downregulating the production of proinflammatory cytokines, antioxidative effects, the suppression of matrix metalloproteinases production, and positive hemodynamic effects.

P2Y12 receptor mediated inhibition of platelet aggregation is one of the most explored and exploited pathways in antiplatelet drug therapy to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI) for the treatment of the acute coronary syndrome (ACS). Ticlopidine, Clopidogrel, Prasugrel, Ticagrelor, Cangrelor and Elinogrel are the P2Y12 inhibitors that act as antiplatelet drugs. In this review, the features of these drugs and the factors reported to be responsible for drug resistance or drug ineffectiveness were described. The features like drug metabolism, reversible or irreversible binding of drugs to their target protein and the mode of administration were observed to evolve along with the antiplatelet drugs. These features also include the drug-drug interactions, the pharmacogenetics and pharmacodynamics of P2Y12 inhibitors. We attempted to critically analyze how the desirable features were met by the P2Y12 inhibitors in the course of time. This review provides an overview of the evolution of P2Y12 inhibitors and may guide the researchers to develop better antiplatelet drugs in the future.

A lower than normal function of the sympathetic nervous system (SNS) has been identified early in the course of multiple sclerosis (MS) and has been shown to play a role in the pathology of the disease. In addition, the chronic use of many drugs commonly used by MS patients could further downregulate SNS by interfering with norepinephrine (NE) synthesis/release and/or interfering with the function of the adrenergic receptors in both the brain and in the periphery. This drug-induced downregulation of SNS activity, when imposed on a background of SNS dysfunction, could not only promote immune inflammatory and neurodegenerative processes, but also can lead to a reduced clinical response to immunomodulaory therapies. Furthermore, low SNS activity could contribute to a higher prevalence of disorders such as depression, fatigue and osteoporosis, which has been observed in MS patients. An algorithm could be constructed based on the combination of baseline NE plasma levels and SNS response levels to a β-adrenergic agonist stimulus. This algorithm, corrected for age and gender, would have the potential to identify MS patients who have a reduced response to immunomodulatory therapies.

Resveratrol found in fruits, vegetables and beverages such as red wine, has been extensively evaluated for its anticardiovascular disease and cancer preventive effects. Even though studies have demonstrated its anti-tumor effects, there is still no clear explanation for cancer cell selective mechanisms of action of resveratrol. Initial investigations were focused on its anti-oxidant and cytoprotective mechanism of action, yet, a large number of studies have demonstrated that resveratrol can behave either as anti-oxidant or pro-oxidant depending on the selective microenvironment. What makes resveratrol a protective agent in normal cells and a radical generator possessing cytotoxic activity against cancer cells is a widely debated topic. There must be certain conditions found in tumors that allow resveratrol to become a pro-oxidant that clearly differs from that found in normal cells. Results of studies from our group have established that many different dietary agents can mobilize intracellular copper ions and in the process, generate reactive oxygen species through Fenton type reactions leading to oxidative DNA breakage and consequently, cell death. More significantly, we demonstrated that such pro-oxidant-induced DNA damage and apoptotic activity are enhanced in low pH environments; characteristically observed in tumors due to preferential dependence on glycolysis or the “Warburg effect”. This review discusses the recent advancements in understanding the pro-oxidant anti-cancer behavior of resveratrol as a dietary chemopreventive agent, explained in the light of the Warburg effect.

HM-3, An RGD (Arg-Gly-Asp)-modified polypeptide derived from endostatin, is a potent angiogenesis inhibitor. Its robust inhibitory effects on endothelial cell migration and tumor growth have been demonstrated by activity assay both in vitro and in vivo. However, HM-3 has relatively short half-life in vivo. In order to prolong its half-life and retain its safety and efficacy, previous studies modified HM-3 with four types of PEG (site-specific N-terminal modification), and the results showed that mPEG-SC20k-HM-3 was the most ideal modification product via activity evaluation in vivo. In the present study, we determined the pharmacokinetic properties, immunogenicity and binding targets of mPEG-SC20k-HM-3. The results showed that mPEG-SC20k-HM-3 had good linear pharmacokinetic properties in SD rats. The half-life of mPEG-SC20k-HM-3 was 43.76-fold longer than that of unmodified HM-3 after intravenous injection in SD rats. The administration frequency of the modified product (mPEG-SC20k-HM-3) was reduced from twice a day to once every 2 days, while the safety and efficacy were retained. The immunogenicity of mPEG-SC20k-HM-3 was significantly lower than that of HM-3 in BALB/c mice. Histochemical and immunohistochemical results showed that mPEG-SC20k-HM-3 could significantly inhibit angiogenesis and tumor growth, induce continuous necrosis, and reduce vessel density within tumor tissues. Furthermore, mPEG-SC20k-HM-3 could bind multi-target αvβ3 and α5β1 of integrin, and the major binding target was integrin αvβ3. All of these results indicated that PEGylated HM-3 had a good application prospect.

Triterpenes have been reported to induce cell death. One relevant group of this family of compounds is cucurbitacins, which have been studied as inducers of apoptosis in various cancer cell lines. The most significant mechanisms with regard to the apoptotic effects of cucurbitacins are their ability to modify transcriptional activities via nuclear factors or genes and their capability to activate or inhibit pro- or anti-apoptotic proteins. Still, while the majority of studies on these compounds have dealt with their apoptotic effects on cancer cell lines, several research groups have also explored their anti-inflammatory activities. In general, cucurbitacins are considered to be selective inhibitors of the JAK/STAT pathways; however, other mechanisms may be implicated in their apoptotic effects, including the MAPK pathway (known to be important for cancer cell proliferation and survival), PARP cleavage, expression of active caspase-3, decreased pSTAT3 and JAK3 levels, as well as decreases in various downstream STAT3 targets such as Mcl-1, Bcl-2, Bcl-xL, and cyclin D3, all of which are implicated in apoptosis and the cell cycle. Taking all these effects into account, cucurbitacins may prove useful in the treatment of different kinds of cancers, especially when used with other cytostatic agents.