Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 11, Issue 1, 2011

Central Nervous System Agents in Medicinal Chemistry continues with its objective of bringing together the different perspectives of scientists with diverse backgrounds in chemistry, biology and pharmacology with the common goal of fostering the development of medicinal chemistry and its integration with growing disciplines in the field of medical sciences. With a careful selection of subjects and up to date reviews, Central Nervous System Agents in Medicinal Chemistry intends to remain as the reference journal in the area of medicinal chemistry reviews. We are confident that the fulfilment of this objective is clearly benefited by the inclusion of CNSA-MC in the widely used Medline/PubMed database. This evolution is made possible thanks to the efforts of all the persons that contribute to the different stages of the journal, from the authors and reviewers to the dedicated technical staff that takes care of the whole elaboration process. I would like to express my gratitude to all of them and assure that we will continue working and doing our best to promote the quality of the journal and to keep its upfront position with growing scope and impact in current science. In this March issue, a panel of leading experts provides overviews about different fields of interest focused on different aspects related to the central nervous system and its pathologies. The important field of cancer in the CNS is addressed by Drs. F. Meriggi and A. Zaniboni with respect to the new avenues for the treatment of leptomeningeal carcinomatosis and by Drs. T. de Cresci, M.T. Serrao, S.R. Rogatto, R. Kaneno, C.H. Braga, P. de Medeiros with their update on the genetic factors involved in the risk of brain tumors. Moving to a different theme focused on the advances of new treatments for CNS pathologies, Drs. P. Singh, J. Jain, R. Sinha, A. Samad, R. Kumar and M. Malhotra discuss the potential of thiosemicarbazone derivatives as anticonvulsant agents; Dr R. Bartzatt reviews the current situation of the small molecule agents for the treatment of Mycobacterium tuberculosis infections in the CNS; Drs. V. Pizza, V. Busillo, A. Agresta, A. Bisogno and A. Capasso assess the ability of levetiracetam for the treatment of migraine in elderly patients; Dr. M. Fornaro makes an in-depth review of the pharmacological management of catatonic syndromes; Drs. F.H. Ebner, E. Darra, S. Mariotto, H. Suzuki and E. Cavalieri describe the potential of STAT1 inhibitors for the treatment of different neurodegenerative diseases and, last but not least, Dr. P. Taupin makes a brief report about the situation of neurogenic drugs and Drs. S. Yasuda, H. Sugiura, H. Tanaka, S. Takigami and K. Yamagata address the ability of p38 MAPK inhibitors to treat a wide variety of neural diseases. I am very grateful to all the above contributors for their excellent reviews and I hope readers will enjoy this issue which represents deep insight and excellent understanding of these CNS related pathologies.

In the etiology of brain injury associated to ischemia/reperfusion (I/R) and neurodegenerative diseases, a critical involvement of excessive activation of signal transducer and activator of transcription 1 (STAT1) and successive induction of iNOS expression has widely been evidenced. Any compound capable to down-regulate STAT1 activation seems to represent a new, promising anti-inflammatory drug. Among plant compounds, only a few have shown to possess anti-STAT1 activity. Among them, epigallocatechin-3-gallate (EGCG), the main polyphenol present in green tea leaves, efficiently protects heart from I/R injury and this action is strictly correlated to its anti-STAT1 property. Hyperforin, the non-polyphenolic compound present in St. John's wort, attenuates β-cell death induced by interferon-γ (IFN-γ) by strongly down-regulating STAT1 activation. STAT1, therefore, seems to represent a new molecular target of the protective treatment also against brain injury associated to a number of brain pathologies. Either understanding the molecular mechanism of anti-STAT1 action of these compounds or identification of other anti-STAT1 compounds are urged.

Some modifying factors may determine the risk of brain tumors. Until now, it could not be attempted to identify people at risk and also to improve significantly disease progression. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. Despite of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed. Mutagen sensivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immunosuppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well established that there is association between brain tumor risk and mutagen sensivity, which is highly heritable. Primary brain tumors cause depression in systemic host immunity; local immunosuppressive factors and immunological characteristics of tumor cells may explain the poor prognosis and DNA damages responses can alert immune system. However, it is necessary to clarify if individuals with both constitutional defects in immune functions and genetic instability have higher risk of developing brain tumors. Cytogenetic prospective studies and gene copy number variations analysis also must be performed in peripheral lymphocytes from brain tumor patients.

In the last years, the hypothesis that cortical hyperexcitability may play a role in the physiopatology of migraine led to the therapeutic use of some antiepileptic drugs. To evaluate the efficacy of levetiracetam as prophylactic treatment for migraine without aura in elderly patients. We performed a small open-label trial treating 13 elderly patients( 8F 5M) mean age 64.7 years (SD 3.4), range 60-72 years affected by migraine without aura (ICDH '04 criteria). The mean age of disease was 21.3 years (SD13.4) range 2-45 years. At baseline: the frequency of attacks was 12.2/month (SD 5.9), range 6-25; the mean number of drugs for acute attacks was 12.6 (SD 6.5) tablets/month. All patients took concomitant medication for other cronic diseases. After recruitment Levetiracetam 500 mg/die was administered for 1 week and 1000 mg/die for six months. The basal frequency of attack was 12,2 (SD 5.9) and 8,3 (SD 4.9), 4,1 (SD2.6), 1,3 (SD1.4) after 1, 3 and 6 months respectively [P=0.079; P<0.0001; P<0.0001].The basal value of intaking drugs for acute attacks was 12,6 (SD 6.5) and 6,7 (SD 4.3), 2,8 (SD 2.2), 1,4 (SD1.7) after 1, 3 and six months respectively [P=0.012; P<0.0001; P<0.0001](T-test analysis). Levetiracetam was well tolerated (7 patients complained somnolence, lack of concentration and gastralgia but none patient withdrew the study). In our study levetiracetam showed a good efficacy in frequency and intensity reduction of headache attack and showed a very good tolerability despite all elderly patients took drugs for concomitant diseases.

Neurological diseases and related conditions affect an estimated 1 billion of individuals worldwide [1]. There is still no cure for neurological diseases and disorders, barely a few treatments more or less efficient. This mandates the design and development of novel paradigms and strategies, to discover and develop new treatments and cures for these diseases. Neurogenesis occurs in the adult brain of mammals primarily in two regions, the dentate gyrus (DG) of the hippocampus and the subventricular zone, in various species including in humans. Neural progenitor and stem cells have been isolated, propagated and characterized in vitro from the adult brain of mammals, including humans. The confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals, opens new avenues and opportunities for treating neurological diseases and injuries [2].

Leptomeningeal Carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases and is a rare presentation of solid tumors, particularly breast cancer, lung cancer and malignant melanoma in adults and hematogenous malignancies and primitive neuroectodermal tumor (PNET) in children. Recently, the incidence of LC has been reported to be increasing due to a longer overall survival obtained in patients treated with novel antineoplastic agents. The usual clinical presentation is a multifocal involvement of the neuraxis, with headache and radicular pain being the most common initial symptoms. The most frequent signs are motor deficits, altered mental status and cranial nerve involvement. The treatment of LC remains controversial and no straightforward guidelines exist in the literature. It has a bad prognosis and inevitably fatal outcome despite aggressive therapy.

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.

A series of thiosemicarbazones of halogen substituted benzaldehydes, benzophenone and acetophenone were synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established in three seizures models which includes maximal electroshock (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizures and minimal neurotoxicity test. Five compounds out of 21 exhibited protection in MES test while only one compound showed protection in scPTZ screen. Two compounds were found to be active in minimal clonic seizure (6Hz) model. Compound PS6 i.e. 2-(3-bromobenzylidene)- N-(4-chlorophenyl) hydrazinecarbothioamide emerged as the most active compound with MES ED50 of more than 50mg/kg and pI greater than 12, which is found to be better than the prototype drug, Phenytoin. The compound has shown neuroprotection in kainic acid model with IC50 value of 40.97 μM. It has also shown mild activation effect on CYP2D6 and CYP 2C9 enzymes, indicating the usefulness of thiosemicarbazones as anticonvulsants.

Tuberculous meningitis is caused by Mycobacterium tuberculosis, which is the bacteria that causes tuberculosis. This bacteria spreads to the brain from another site within the body. If untreated, tuberculous meningitis can be lifethreatening. Substantial brain damage can result from infection which results in mental impairment, motor paralysis, seizures, and abnormal behavior. This study presents the analysis of the effectiveness of 13 novel tuberculostatic agents, along with isoniazid (a first-line drug utilized for treatment of Mycobacterium tuberculosis). All 13 agents retain a diverse character of molecular structure effectuating a range of molecular properties such as in polar surface area, Log P, and formula weight. Properties such as polar surface area, formula weight, and Log P were determined for these agents as well as values of BB (Cbrain/Cblood), and Log BB. Values of BB varied from 0.0681 to 1.16. Only three of the novel drug structures showed one violation of the Rule of 5, while the remaining showed zero violations (an outcome favoring bioavailability). Values of polar surface area ranged from 55.121 Angstroms2 to 110.24 Angstroms2, and Log P from -3.52 to 4.965. This group of novel tuberculostatic agents reveals examples of three homologous series of tuberculostatic drugs which purposes the likelihood of as many as 20 effective tuberculostatic drugs. Determination of MIC60 disclosed eight novel structures matching the effectiveness of isoniazid, while two showed superior ability to deter Mycobacterium tuberculosis proliferation. These novel drug designs are shown to have substantial potential for the beneficial treatment of patients having infections of Mycobacterium tuberculosis within the central nervous system.

Catatonic syndromes involve a complex mixture of motor, behavioral, and systemic manifestations that are derived from unclear mechanisms. What is clear is that neurotransmitters, such as dopamine (DA), gamma-aminobutyric acid (GABA), and glutamate (GLU), are of major importance in the pathogenesis of catatonia and Neuroleptic Malignant Syndrome (NMS) and that serotonin (5-hydroxytryptamine [5-HT]) is crucial to the development of Serotonin Syndrome (SS). As medications with potent effects on modulation of monoamines proliferate, the diagnosis and management of these complex disorders become even more important. Without question, these syndromes have signs, symptoms and treatments that overlap, thus, considering the symptomatological load and the associated clinical burden (including potentially life-threatening conditions), the need for a better knowledge of the hypothesized biological mechanisms and pharmacological management is imperative. Although the search for a unique, conclusive approach to the management of catatonia is futile, stating the heterogeneity of the clinical pictures and the wide range of effective treatment choices (including non-pharmacological interventions), clinicians should not disregard an accurate, critical therapeutic approach to such a relevant, yet often disregarded, topic. The aim of this narrative review is to provide both clinicians and pharmacologists with a narrative, panoramic review on catatonia and associated clinical pictures, focusing on its general pharmacological management.