Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 11, Number 1, March 2011
Contents
Editorial: Pp. 1
Use of STAT1 Inhibitors in the Treatment of Brain I/R Injury and neurodegenerative Diseases Pp. 2-7
F.H. Ebner, E. Darra, S. Mariotto, H. Suzuki and E. Cavalieri
[Abstract] [Purchase
Article] [PMID:
20812906 PubMed - indexed for MEDLINE]
Genetic and Modifying Factors that Determine the Risk of Brain Tumors Pp. 8-30
Terezinha de Cresci Braga Montelli, Maria Terezinha Serrão Peraçoli, Silvia Regina Rogatto,
Ramon Kaneno, Cíntia Helena Braga Montelli do Prado and Patrícia de Medeiros Cardassi Rocha
[Abstract] [Purchase
Article] [PMID:
20528763 PubMed - indexed for MEDLINE]
Elderly Patients with Migraine: An Open-Label Study on Prophylaxis Therapy with Levetiracetam
Pp. 31-34
V. Pizza, V. Busillo, A. Agresta, A. Bisogno and A. Capasso
[Abstract] [Purchase
Article] [PMID:
21250937 PubMed - indexed for MEDLINE]
Neurogenic Drugs and Compounds to Treat CNS Diseases and Disorders Pp. 35-37
Philippe Taupin
[Abstract] [Purchase
Article] [PMID:
21250936 PubMed - indexed for MEDLINE]
Newer Avenues for the Treatment of Leptomeningeal Carcinomatosis Pp. 38-44
Fausto Meriggi and Alberto Zaniboni
[Abstract] [Purchase
Article] [PMID:
21250935 PubMed - indexed for MEDLINE]
p38 MAP Kinase Inhibitors as Potential Therapeutic Drugs for Neural
Diseases Pp. 45-59
S. Yasuda, H. Sugiura, H. Tanaka, S. Takigami and K. Yamagata
[Abstract] [Purchase
Article] [PMID:
20812905 PubMed - indexed for MEDLINE]
Synthesis and Screening of Substituted Thiosemicarbazone Derivatives:
An Approach towards Novel Anticonvulsant Search
Pp. 60-65
Priyanka Singh, Jainendra Jain, Reema Sinha, Abdul Samad, Rajeev Kumar and Manav Malhotra
[Abstract] [Purchase
Article] [PMID:
21294704 PubMed - indexed for MEDLINE]
Properties and Potency of Small Molecule Agents for Treatment of Mycobacterium
Tuberculosis Infections of the Central Nervous System
Pp. 66-72
Ronald Bartzatt
[Abstract] [Purchase
Article] [PMID:
21294705 PubMed - indexed for MEDLINE]
Catatonia: A Narrative Review
Pp. 73-79
Michele Fornaro
[Abstract] [Purchase
Article] [PMID:
21294706 PubMed - indexed for MEDLINE]
Abstracts
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Article] [PMID:
20812906 PubMed - indexed for MEDLINE]
Use of STAT1 Inhibitors in the Treatment of Brain I/R Injury and Neurodegenerative Diseases
F.H. Ebner, E. Darra, S. Mariotto, H. Suzuki and E. Cavalieri
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.
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20528763 PubMed - indexed for MEDLINE]
Genetic and Modifying Factors that Determine the Risk of Brain Tumors
Terezinha de Cresci Braga Montelli, Maria Terezinha Serrão Peraçoli, Silvia Regina Rogatto,
Ramon Kaneno, Cíntia Helena Braga Montelli do Prado and Patrícia de Medeiros Cardassi Rocha
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.
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[PMID:
21250937 PubMed - indexed for MEDLINE]
Elderly Patients with Migraine: An Open-Label Study on Prophylaxis Therapy with Levetiracetam
V. Pizza, V. Busillo, A. Agresta, A. Bisogno and A. Capasso
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.
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21250936 PubMed - indexed for MEDLINE]
Neurogenic Drugs and Compounds to Treat CNS Diseases and Disorders
Philippe Taupin
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].
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21250935 PubMed - indexed for MEDLINE]
Newer Avenues for the Treatment of Leptomeningeal Carcinomatosis
Fausto Meriggi and Alberto Zaniboni
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.
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20812905 PubMed - indexed for MEDLINE]
p38 MAP Kinase Inhibitors as Potential Therapeutic Drugs for Neural
Diseases
S. Yasuda, H. Sugiura, H. Tanaka, S. Takigami and K. Yamagata
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.
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21294704 PubMed - indexed for MEDLINE]
Synthesis and Screening of Substituted Thiosemicarbazone Derivatives:
An Approach towards Novel Anticonvulsant Search
Priyanka Singh, Jainendra Jain, Reema Sinha, Abdul Samad, Rajeev Kumar and Manav Malhotra
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.
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Properties and Potency of Small Molecule Agents for Treatment of Mycobacterium
Tuberculosis Infections of the Central Nervous System
Ronald Bartzatt
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.
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Catatonia: A Narrative Review
Michele Fornaro
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.
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