Hari Manev

University of Illinois Chicago

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Tolga Uz

University of Illinois Chicago

Radmila Manev

University of Illinois Chicago

Svetlana Dzitoyeva

Federal State Budgetary Institution of Science Federal Scientific Center "Vladikavkaz Scientific Center of the Russian Academy of Sciences"

Marta Imbesi

Northwestern University

Nikola Dimitrijević

Metropolitan University

Danka Peričić

Rudjer Boskovic Institute

Marco Favaron

Alessandro Manzoni Hospital

Pietro Giusti

University of Padua

Alessandro Guidotti

University of Bologna

Alexander Kharlamov

Rotterdam University of Applied Sciences

Cooperative Institutions

University of Illinois Chicago

University of Illinois Urbana-Champaign

University of Padua

Fidia Farmaceutici (Italy)

Rudjer Boskovic Institute

Georgetown University

Johns Hopkins University

University of Zagreb

University of Chicago

Illinois College

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Cardiovascular-CNS Comorbidity as a Means to Rationalize Serendipity in Drug Discovery and Advance Translational Research

Cardiovascular Psychiatry and Neurology (2010)

Hari Manev

It has been argued that “lamp-post research” is the main culprit in the lack of major breakthroughs in neuropsychiatric drug discovery. An old joke goes like this. A drunk loses his keys and looks for them under a lamp-post. A passerby asks what he is doing. He answers: “Looking for my keys that I lost in a dark alley two blocks away.” “Then why are you looking for them under this lamp-post?” wonders the passerby. “Because I can see much better here.” Not all researchers looking for novel neuropsychiatric pharmacological treatments are all drunks, but the alternative to lamp-post research (which mostly generates “me-too” drugs rather than entirely new compounds) appears to be even less rational—it typically involves serendipity. Several strategies have been proposed to overcome reliance on pure serendipity, which occurs too rarely to be counted on as a consistent source of drug discovery. These strategies include cell-phenotype-based and organism-phenotype-based approaches to the rationalization of serendipity for drug discovery. Phenotype-based approaches to drug discovery rely on the notion that putative therapeutic molecules can be discovered in the absence of any knowledge about a disease mechanism (i.e., molecular target) if these molecules are capable of reversing a disease phenotype. A historical example of serendipitous organism-phenotype-based approach is the discovery of the first antidepressant agents. Briefly, in the search for a tuberculostatic at the end of World War II, stocks of the leftover rocket propellant hydrazine were used to produce its chemical derivatives, isoniazid and iproniazid, which were found to be potently tuberculostatic. Physicians who more than 60 years ago used these drugs for treatment of tuberculosis observed that, in addition to the healing of tubercular lesions, isoniazid and even more so, iproniazid, produced favorable mental “side effects.” This serendipitous organism-phenotype-based discovery led to the testing of iproniazid in depressed patients and finding its antidepressant action. Recent indications of putative mechanisms responsible for the cooccurrence of cardiovascular and psychiatric/neurological disorders point to an additional possibility for improving the process of serendipity rationalization in drug discovery—by focusing on the cooccurrence of these disorders. As an example, one could focus on the cooccurrence of major depression (MD) and coronary heart disease (CHD), in which depression is independently associated with increased cardiovascular morbidity and mortality. Serendipity could be rationalized by specifically targeting patients with cooccurring MD and CHD (or alternatively using animal models of this cooccurrence) and applying the CHD-phenotype-based approach in evaluating drugs (standard or novel/experimental) administered primarily for the treatment of the MD component of the cooccurrence. A successful screen performed in this manner could lead to the discovery of novel families of cardiovascular drugs. Alternatively, one could use the MD-phenotype-based approach in evaluating drugs for the treatment of the CHD component of this cooccurrence to find novel antidepressants. For such an approach to be successful, no initial knowledge is required about the putative mechanistic links between MD and CHD. Once effective drugs/molecules are identified, this knowledge could be used to elucidate the participating biological/molecular mechanisms. Similar approaches could be developed for other cooccurring cardiovascular and psychiatric/neurological disorders. The current establishment of a new network of NIH- (National Institutes of Nealth-) supported Clinical and Translational Research Centers (CTSCs) in the USA emphasizes a renewed interest in fostering closer ties between basic and clinical research. If these ties succeed in rationalizing serendipity in the search for novel neuropsychiatric and cardiovascular pharmacological treatments, the new CTSCs could prove to be a way out of discredited lamp-post research and also a way to stop relying on the serendipitous discoveries that have proved so scarce in the past. Cardiovascular Psychiatry and Neurology looks forward to the results of these future studies. Hari Manev

Serendipity

Translational Research

10.1155/2010/318167

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Citations (0)

5-Lipoxygenase as a Putative Mechanism of NSAID-Related Psychiatric Adverse Events

Drugs (2005)

Radmila Manev Hari Manev

Pharmacotherapy

10.2165/00003495-200565040-00009

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Citations (5)

In vivo protection against kainate-induced apoptosis by the pineal hormone melatonin: effect of exogenous melatonin and circadian rhythm

Restorative Neurology and Neuroscience (1996)

Hari Manev Tolga Uz Alexander Kharlamov Cinzia Cagnoli Davide Franceschini

We recently reported that the pineal hormone melatonin protected neuronal cultures from excitotoxicity mediated via kainate-sensitive glutamate receptors and from oxidative stress-induced apoptosis. It has been shown that in rats, a systemic administration of kainate induces apoptotic cell death in various brain regions. In this study, we assayed the extent of brain injury after intraperitoneal (i.p.) administration of 10 mg/kg kainate to rats, using the quantitative TUNEL technique and Nissl staining. We examined the role of melatonin on kainate-induced brain injury by (a) injecting melatonin (4 × 2.5 mg/kg i.p.) prior to and after kainate injection and (b) injecting kainate at the time of low circulating melatonin levels (day/light), and high melatonin levels (night/dark). The extent of kainate-triggered DNA damage and the loss of Nissl staining were lower in animals treated with melatonin, or when kainate was injected at night, i.e. in the presence of high endogenous levels of melatonin. Our results suggest that both the pharmacological use of melatonin and the circadian secretion of endogenous melatonin during the night may reduce the extent of excitotoxic brain injury. Further studies are needed to fully characterize the relevance of our findings for the treatment of progressive neurodegenerative processes which involve excitotoxicity and apoptotic neuronal death.

Kainate receptor

Excitotoxicity

Nissl body

10.3233/rnn-1996-9408

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Citations (36)

Melatonin protects from kainate-induced neurotoxicity

Behavioural Pharmacology (1995)

Milena Gusella Maria Lipartiti Davide Franceschini Hari Manev Pietro Giusti

Dept. Pharmacology, University of Padova; 1ASRI, Medical College of Pennsylvania, Pittsburgh, PA 15212, USA.

Kainate receptor

Neurotoxicity

10.1097/00008877-199505001-00115

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Citations (2)

Brain monoamines and plasma corticosterone in stressed rats treated with dextroamphetamine or propranolol.

PubMed (1982)

Danka Peričić Hari Manev Milivoj Boranić Marija Poljak‐Blaži

Dextroamphetamine

Corticosterone

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Citations (3)

The Heart-Brain Connection Begets Cardiovascular Psychiatry and Neurology

Cardiovascular Psychiatry and Neurology (2009)

Hari Manev

In many Asian languages, the same ancient letter/symbol is used for heart and mind. For the last couple of millennia, physicians and scientists across different civilizations have posited close links between the brain and heart, even arguing that the site of intelligence and emotions is in one of these two organs. Through an integrative empirical approach in modern biology/physiology and behavioral sciences, much has since been learned to confirm the anatomical and functional links between the brain and the heart. Arguably, the ultimate applicability of this knowledge will advance our health and improve disease treatment. Modern medicine is characterized by a high degree of specialization, and the heart-brain connection is typically considered from the point of view of a particular medical specialty. Hence, focusing on the brain, for example, in neurology, cardiovascular involvement is critical in certain pathologies such as stroke and vascular dementia. In cardiology, on the other hand, the influence of the brain becomes clearly apparent in “the broken heart syndrome” (also known as acute stress cardiomyopathy). However, recent epidemiological studies point to new associations that typically present as co-occurring pathologies of both the brain and the heart. A case in point is the association between depression and coronary heart disease. Such co-occurrences have stimulated research into possible novel mechanisms that could be targeted to treat these complex cardiovascular/brain disorders. At least three scenarios could be at play in these illnesses: (i) the primary pathological mechanism in the nervous system triggers a cardiovascular pathology by disrupting physiological links between the two systems (hence, the term “psychogenic”cardiovascular disease), (ii) the primary pathological mechanism in the cardiovascular system triggers a nervous system dysfunction (e.g., atherosclerosis leading to ischemic conditions causes subsequent cognitive impairment), and (iii) the primary pathology is in a biological mechanism that is normally operative in both the nervous and the cardiovascular systems, thus causing the co-occurrence of pathologies (i.e., the co-occurring pathologies share a pathobiological mechanism but do not necessarily cause each other). To be successful, research in co-occurring cardiovascular and brain disorders needs contributions from multiple medical specialties, including psychiatry, neurology, medicine, and cardiology. It should encompass clinical and basic research as well as the development of therapeutic approaches. The purpose of Cardiovascular Psychiatry and Neurology is to provide a platform for the latest research and for timely and expert reviews and comments in the emerging field of cardiovascular psychiatry and neurology. Although the term cardiovascular psychiatry and neurology is introduced here for the first time, retrieving publications from PubMed using either cardiovascular psychiatry or cardiovascular neurology generates relevant information (oftentimes because the terms psychiatry or neurology appear in the tile of a journal publishing the work). A quick survey of PubMed for the publication period from 1940 to 2008 (Table 1) revealed, not surprisingly, that the number of items per search term has increased dramatically over the years. Whereas the term cardiovascular showed a sharp increase in the early sixties, both neurology and psychiatry “exploded” in the early nineties. Even though the term cardiovascular psychiatry appeared earlier than cardiovascular neurology, the later term has become more prevalent since the early sixties (Table 1). Normalizing the data, that is, by expressing cardiovascular psychiatry as a percentage of corresponding psychiatry and cardiovascular neurology as a percentage of the corresponding neurology (Figure 1), showed that cardiovascular neurology rose sharply in the early sixties and has remained at about 5% of all neurology-related items. On the other hand, cardiovascular psychiatry had been below 1% of all psychiatry-related items until the early eighties, but has gradually increased. Possibly, the ischemia-related brain disorders have contributed to the relatively high presence of cardiovascular neurology and the relatively recent revelation of an unsuspected association of cardiovascular disorders with mood disorders might have contributed to the increase in cardiovascular psychiatry. The journal Cardiovascular Psychiatry and Neurology was created to provide for the first time a unified forum to consider the physiological and pathological interactions between the nervous and the cardiovascular systems. The journal aims to stimulate the development of relevant interdisciplinary and collaborative biomedical research and to foster multidisciplinary efforts in advancing medical practices. Figure 1 The proportions of retrieved PubMed terms Cardiovascular Psychiatry versus Psychiatry and Cardiovascular Neurology versus Neurology. The PubMed search was performed as described in Table 1. The percentages of items found for Cardiovascular Psychiatry ... Table 1 A number of PubMed items retrieved on January 13, 2009. The terms indicated in the table were searched (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed) for the indicated publication dates (years). No systematic checking was performed for the actual ... Hari Manev

10.1155/2009/546737

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Citations (6)

Drosophila metabolize 1,4-butanediol into γ-hydroxybutyric acid in vivo

European Journal of Pharmacology (2003)

Rosalba Satta Nikola Dimitrijević Hari Manev

1,4-Butanediol

2,3-Butanediol

10.1016/s0014-2999(03)01993-9

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Citations (18)

GABA-B Receptors in Drosophila

Advances in pharmacology (2010)

Hari Manev Svetlana Dzitoyeva

Class C GPCR

GABAB receptor

Neuropharmacology

Gamma-Aminobutyric Acid

10.1016/s1054-3589(10)58017-7

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Citations (10)

Role of melatonin receptors in the effects of melatonin on BDNF and neuroprotection in mouse cerebellar neurons

Journal of Neural Transmission (2008)

Marta Imbesi Tolga Uz Hari Manev

Knockout mouse

10.1007/s00702-008-0066-z

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Citations (32)

Drug- and region-specific effects of protracted antidepressant and cocaine treatment on the content of melatonin MT(1) and MT(2) receptor mRNA in the mouse brain.

PubMed (2006)

Marta Imbesi Tolga Uz Sevim Yildiz Ahmet Arslan Hari Manev

OBJECTIVES: In the mammalian brain, G protein-coupled MT(1) and MT(2) melatonin receptors may be involved in Alzheimer's pathology, long-term potentiation, depression, and in the behavioral effects of psychoactive drugs. These drugs; e.g. antidepressants and drugs of abuse, are typically used over long periods of time and may alter neuroplasticity and gene expression. We hypothesized that such antidepressant- and cocaine-altered expression of melatonin receptor mRNA may occur in the hippocampus and striatum. METHODOLOGY: Male C3H/HeJ mice were treated with the antidepressants fluoxetine, desipramine, and clomipramine, with the psychostimulant cocaine, and with a vehicle either a single time or once a day for 14 days. Brain samples were collected 24 h after the last injection and the content of MT(1) and MT(2) mRNA was assayed. RESULTS: A single drug injection did not alter the MT(1) and MT(2) mRNA content. In the hippocampus, protracted treatment with antidepressants increased the amount of MT(1) mRNA (with the exception of fluoxetine) but decreased MT(2) mRNA content; cocaine did not produce any alterations. In the striatum, antidepressants produced the opposite effect on MT(1) mRNA content; they decreased it. They did not significantly alter striatal MT(2) mRNA (we observed a nonsignificant trend to a decrease). Cocaine also decreased striatal MT(1) mRNA content without affecting MT(2) mRNA. CONCLUSION: These results suggest that drug- and region-specific alterations of MT(1)/MT(2) mRNA produced by protracted antidepressants and cocaine treatment may alter MT1/MT2 expression and contribute to long-term neuroplastic effects of these drugs.

Desipramine

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Citations (31)