Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 11, Issue 4, 2011

Failures in the control of infectious diseases in tropical and developing countries are a major challenge for research, such as, diseases that are not preventable by vaccination and which depend on successfully health and social policies. Some of these uncontrolled diseases are now reaching the developed world. Increasing temperatures of the world facilitate conditions for new vectors establishment and disease pathogens transmission, such as malaria, arbovirus and cysticercosis. Neglected infectious diseases have a higher prevalence in tropical regions, where temperature ranges from 15°C to 40°C. Populations living in these regions are considered the poorest people in the world and poverty is associated with infectious disease prevalence. Tropical infections that may compromise Central Nervous System, beyond human suffering and death, cause disability, economic, social and political impact. In this hot issue, we focus neurological infectious diseases in which control strategies have failed and therapy is still an unresolved question. First, Prof. Dr. Jorge Casseb (Institute of Tropical Medicine of Sao Paulo, SP, Brazil) and coworkers, give an update on HTLV-1-associated myelopathy. The pathogenesis and therapies with histone deacetylase inhibitor, interferon-alpha, vitamin C and glucorticoids are in depth discussed. In recent years, neurotuberculosis has become a formidable challenge, showing high morbidity and mortality. Prof. Dr. Thais Soares Cianciarullo Minett (Public Health and Primary Care, Cambridge University, Cambridge, UK and Department of Preventive Medicine - Federal University of Sao Paulo, Sao Paulo, Brazil), wrote an up-to-date and complete review about this common and dangerous disease. This article may help physicians to decide when to initiate specific therapy even without a definitive diagnosis. The wide variety of clinical manifestations and lesions to the Central Nervous System is described and thoroughly demonstrated in MRI scans. Indicators of prognosis, such as ages, clinical staging at admission and also the prevention with BCG vaccine, are critically described and discussed. Prof. Dr. Svetlana Agapejev (Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, SP, Brazil) made a full review about Neurocysticercosis that indeed describes all the main aspects of this terrible disease. Several important and less known findings of the own author research, are exposed, such as: the existence of asymptomatic forms; the importance of clinical polymorphisms; the presence of chronic brain edema that may cause psychic alterations; the standardization of the normal values of the fourth ventricle size and comparison with patient's values; the association of clinical findings with these altered indexes; proved the existence of re-infections; recommendations of high dosages of drugs for treatment and the presence of “glucose zero” in CSF, associated with cysts and diffuse edema. Prof. Dr. Antonio Lucio Teixeira et al. (Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil) provide a complete overview of the current literature and of his own researches about Cerebral Malaria. Cognitive dysfunctions in experimental and in human clinical studies are described. Therapy with neuroprotective drugs, that is a recent research focus, in order to improve cognitive outcome, is also discussed. Indeed, it is a review paper with a translational scientific feature. Prof. Dr. Mauricio L. Nogueira et al. (Laboratorio de Pesquisa em Virologia, Faculdade de Medicina de Sao Jose do Rio Preto, Sao Jose do Rio Preto, SP, Brazil) wrote an overview about arboviral encephalitis, mainly Venezuelan Equine Encephalitis Virus, Western Equine Encephalitis Virus, Eastern Equine Encephalitis, Japanese Encephalitis Virus, West Nile Fever Virus, Saint Louis Encephalitis Virus and Dengue Virus. West Mile virus, Dengue Virus and Japanese Encephalitis Virus have spread worldwide in recent years. Moreover, they discussed the potential therapeutic applications of RNA interference technology in order to inhibit viral replication. We hope that this hot-topic issue on Tropical Neurology may be useful to improve research and clinical attendance in tropical and developed countries.

Human T-cell leukemia virus type 1 (HTLV-1) is the ethiologic agent of the neurological disorder HTLV-1- associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic during their lifetime, approximately one percent of this population develops a myelopathy consisting of a chronic inflammation of the white and gray matter of the spinal cord. Glucocorticoids are widely used for treatment because of their anti-inflammatory properties, improving symptoms mainly in those patients with only a few years from onset of the disease, when inflammation is more prominent. Interferon-alpha and vitamin C are other therapies presenting some benefits in clinical practice, probably due to their anti-viral and immunomodulatory activities observed ex vivo. Furthermore, inhibitors of histone deacetylase, which increase virus expression but result in a substantial decline in the proviral load, have also been proposed. This review is intended to bridge the gap between clinical and basic science by presenting recent findings on HAM/TSP disease, mechanisms of drug action, and benefits of these therapies in HAM/TSP patients.

Although pulmonary tuberculosis is the most common form of this disease, neurotuberculosis is more severe and presents higher morbidity and mortality. Its diagnosis continues to challenge physicians all over the world. Contributing to this fact is the nonspecificity of its clinical manifestations, the low density of bacilli in the cerebrospinal fluid (CSF), and the delayed recovery of Mycobacterium tuberculosis through culture techniques. Thus, the diagnosis is largely based on suspicious symptoms, and the prognosis is directly related to the stage of the disease at the beginning of treatment. Even thought there is no consensus regarding the best therapeutic regimen, the WHO recommends using the same regimen used for pulmonary tuberculosis with a longer treatment time. It is important to note that in most cases, the doctor will not have a definite diagnosis at the beginning of the treatment. However, this should not delay the initiation of therapy. A delay in initiating treatment, in most cases, is directly associated with a poor prognosis. This review gives an overview of the current state of the neurotuberculosis research. It covers the epidemiological aspects of the infection, pathogenesis, principal clinical presentations, diagnosis highlighting neuroimaging, where a series of imaging are presented, prognosis, prevention and therapeutic regimens.

Neurocysticercosis (NCC) is an infection of the central nervous system (CNS) caused by the metacestode larval form of the parasite Taenia sp. Many factors can contribute to the endemic nature of cysticercosis. The inflammatory process that occurs in the tissue surrounding the parasite and/or distal from it can result from several associated mechanisms and may be disproportionate with the number of cysts. This discrepancy may lead to difficulty with the proper diagnosis in people from low endemic regions or regions that lack laboratory resources. In the CNS, the cysticerci have two basic forms, isolated cysts (Cysticercus cellulosae = CC) and racemose cysts (Cysticercus racemosus = CR), and may be meningeal, parenchymal, or ventricular or have a mixed location. The clinical manifestations are based on two fundamental syndromes that may occur in isolation or be associated: epilepsy and intracranial hypertension. They may be asymptomatic, symptomatic or fatal; have an acute, sub-acute or chronic picture; or may be in remission or exacerbated. The cerebrospinal fluid (CSF) may be normal, even in patients with viable cysticerci, until the patients begin to exhibit the classical syndrome of NCC in the CSF, or show changes in one or more routine analysed parameters. Computed tomography (CT) and magnetic resonance imaging (MRI) have allowed non-invasive diagnoses, but can lead to false negatives. Treatment is a highly controversial issue and is characterised by individualised therapy sessions. Two drugs are commonly used, praziquantel (PZQ) and albendazole (ABZ). The choice of anti-inflammatory drugs includes steroids and dextrochlorpheniramine (DCP). Hydrocephalus is a common secondary effect of NCC. Surgical cases of hydrocephalus must be submitted to ventricle-peritoneal shunt (VPS) immediately before cysticidal treatment, and surgical extirpation of the cyst may lead to an absence of the surrounding inflammatory process. The progression of NCC may be simple or complicated, have remission with or without treatment and may exhibit symptoms that can disappear for long periods of time or persist until death. Unknown, neglected and controversial aspects of NCC, such as the impaired fourth ventricle syndrome, the presence of chronic brain oedema and psychic complaints, in addition to the lack of detectable glucose in the CSF and re-infection are discussed.

Cerebral Malaria (CM) is a clinical syndrome defined by the World Health Organization (WHO) as a potentially reversible diffuse encephalopathy characterized mainly by coma and the presence of asexual forms of Plasmodium falciparum parasites in peripheral blood smears in the absence of other causes of encephalopathy. A wide range of clinical manifestations follows the disease including cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM pathogenesis remain incompletely understood although vascular, immunological and metabolic changes have been described. The classical treatment of CM is based on the administration of antimalarial drugs, especially chloroquine and artemisinin derivates as artesunate. Even with treatment, 15 to 20% of children with CM die and approximately 10 to 17% of those who survive remain with significant long-term cognitive impairment. In this context, neuroprotective and adjuvant therapies have been recently investigated in clinical and experimental studies of CM in an attempt to improve cognitive outcome. A poor understanding of pathophysiological mechanisms, properties of compounds used and patient selection have contributed to the lack of success of these interventions. This review discusses clinical aspects of cognitive sequelae, possible mechanisms involved in the brain injury, perspectives and limitations regarding the pharmacological strategies to improve cognitive outcome in CM.

Encephalitis refers to an acute, usually diffuse, inflammatory process affecting the brain. The clinical hallmark of acute encephalitis is the triad of fever, headache, and altered mental status. The most common and important cause of encephalitis is the infection by a virus although other organisms can cause the disease. This article is a general overview of the most common viral encephalitides, divided into two families, Flavivirus and Alphavirus, and provides details about virus and RNA interference. More detailed descriptions of each viral family are provided bellow.

L-DOPA is the gold standard medication of Parkinson's disease, a neurological disorder consequent upon the degeneration of mesencephalic dopaminergic neurons. The therapeutic efficacy of L-DOPA has been related to its ability to restore dopamine (DA) extracellular levels in the Parkinsonian brain. The origin of the L-DOPA-induced rise in DA has been the object of numerous studies and controversies but the data collectively point to serotonergic (5-HT) neurons as being most significant in the release. Here, we review biochemical and behavioral evidence supporting serotonergic neurons as playing the main role in the actions of L-DOPA, considered from two points of view. The main aspect concerns the biochemical demonstration that 5-HT neurons are almost solely implicated in the release of DA induced by L-DOPA. The mechanism of action of L-DOPA inside 5-HT neurons will be thoroughly dissected on the basis of L-DOPA effects on extracellular versus tissue DA levels. The unique contribution of 5-HT neurons in mediating the release of newly synthesised DA from L-DOPA will be discussed in parallel with DA-dependent behaviors induced by L-DOPA. The other, and neglected, aspect concerns the possible deleterious impact of the presence of L-DOPA inside 5-HT neurons on 5-HT neuronal function. Overall, the fact that 5-HT neurons release the newly synthesised DA from L-DOPA in multiple brain regions beyond the striatum gives new insight into the large impact of L-DOPA in the Parkinsonian brain and strengthens therapeutic perspectives targeting the 5-HT system to reduce both motor and non-motor complications of L-DOPA medication.

The causative agent of Tuberculosis meningitis is Mycobacterium tuberculosis, which is the bacteria that causes pulmonary tuberculosis. Proliferating into the central nervous system occurs from other sites of infection within the body. Brain damage can result from the infection that may lead to abnormal behavior, mental impairments, motor type paralysis, and seizures. Tuberculosis infections of the central nervous system are a serious and often fatal disease predominantly impacting young children, and is thought to be the most devastating form of the disease. Isoniazid is the only first line bactericidal agent that easily crosses the blood-brain barrier and achieves concentrations in cerebrospinal fluid similar to those in serum. Rifampicin, ethambutol, and streptomycin all penetrate into the cerebrospinal fluid poorly, and even in the setting of meningeal inflammation. As much as one-third of the current world's population may be infected with tuberculosis. Tuberculosis infection of the central nervous system is a serious type of extrapulmonary proliferation of this disease . In developing countries, it has high predominance in children. Pathological manifestations of cerebral tuberculosis occur, of which the most common is tuberculous meningitis, followed by tuberculoma, tuberculous abscess, cerebral miliary tuberculosis, tuberculous encephalopathy, tuberculous encephalitis, and tuberculous arteritis. Brain abscesses of Mycobacterium tuberculosis can induce seizures and coma leading to death and complicated due to multiorgan failure. Rapid diagnosis and early intervention is vital for successful outcome for patients. Further studies are required to understand the proliferation of tuberculosis meningitis in addition to the elucidation of new therapeutic drugs for the successful clinical treatment of this deadly disease.