Central Nervous System Agents in Medicinal Chemistry - Volume 8, Issue 4, 2008

The central nervous system (CNS) is more complex in primates, including humans, than in other mammals. Primates have particularly larger, visual, prefrontal, parietal, and temporal cortices. This expansion may cause the higher visual and learning abilities. Furthermore, transient increases in axons and synapses are unique characteristics in the primate neocortex during development. To understand these processes from the molecular level, we have focused on growthassociated proteins, GAP-43 and SCG-10 and on neurotrophins such as BDNF and its TrkB receptor. We have found that the development of truncated TrkB, which lacks the tyrosine kinase domain, correlated well with the downregulation of GAP-43 and SCG-10 expression. This downregulation seems to result in the elimination of axons in primate neocortices during development. The highest levels of BDNF protein in the primate visual and prefrontal cortices occur between 1 and 6 months of age, when the number of synapses is highest, suggesting that BDNF is a candidate molecule for the development of synapses in the primate neocortex. In aging primates, expression of BDNF and somatotstatin (SRIF) decreased and Aβ peptides accumulated. Similar cellular and molecular changes have been found in the brains of patients with Alzheimer's disease, suggesting that aged monkeys are good model animals for this disease. Furthermore, gene therapies for various neurotrophins may be used in the future to cure neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia.

Cefepime is a parenteral fourth-generation cephalosporin antibiotic with an extended spectrum of antimicrobial activity, active against many grampositive and gram-negative bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. It is excreted primarily unchanged in the urine, its half-life is 2 hours in normal renal function, increasing to 13.5 hours as renal function declines. Dosage adjustment for renal insufficiency has been recommended in order to prevent drug accumulation, which may result in adverse drug events. Nevertheless, cefepime can produce neurotoxic manifestations, like epileptic seizures, confusion, tremor, ataxia and agitation, probably mediated by the inhibition of gamma amino butyric acid (GABA) A-receptors. Cefepime neurotoxicity usually begins within 20 hours to 5 days ofdrug exposition. Clinical picture may resolve after withdrawal of the antibiotic, depending on the severity of signs and symptoms, and the time spent to start treatment. The role of electroencephalogram in the diagnosis of cefepime-induced encephalopathy and in the differential diagnosis with other causes of coma is remarkable. When a patient on cefepime develops progressive neurological symptoms, drug neurotoxicity should be considered, early detected and promptly managed. Future experimental studies focusing on the cefepime-GABAA receptors and transporters interactions should shed some light on the pathophysiology of this now well-known condition.

Transcranial magnetic stimulation (TMS) is a safe and easy technique for stimulating neurons in the human central nervous system. Studies combining TMS with drugs in healthy subjects and patients have advanced our knowledge of how TMS activates brain circuits and led to new techniques for evaluating the function of specific systems. For example, TMS techniques can detect effects on axon membranes, glutamatergic and GABAergic synapses and the influence of catecholaminergic systems, as well as group differences due to genetic variations in the response to drugs. With this knowledge base, TMS can now be used to explore and compare the effects of drugs on brain systems and may also serve as a surrogate for behavioral responses in clinical trials.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. To date, there is no cure for this disease. The FDA approved drugs, cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) and an N-methyl-Daspartate receptor antagonist (memantine) for the treatment of AD are symptomatically effective to some patients for short periods of time. Cholinesterase inhibitors exert additional pharmacological action beyond inhibition of cholinesterase that may maximize and prolong the effective of these drugs. The complexity of AD pathogenesis limits these drugs to correct every aspect of the disease. This problem has led to the current challenge in drug discovery to develop multitarget or combinational therapy. EGb 761 is a standardized extract of Ginkgo biloba leaves and has been shown to have potential benefit effects in various models of AD. Combination drug therapy, the use of drugs that act at different targets, may offer a novel strategy for management of AD. In this review, we evaluate mechanisms of individual drugs for treatment of AD and summarize the combination studies between cholinesterase inhibitors and NMDA receptor antagonist memantine, cholinesterase inhibitors and EGb 761 in experimental models and clinical trials.

Alpha-methyl-para-tyrosine (AMPT) temporarily inhibits tyrosine hydroxylase, the rate limiting step in the dopamine biosynthesis cascade. AMPT has been approved for clinical use in phaeochromocytoma in 1979. Recently however, AMPT has been increasingly employed as a pharmacological challenge in acute dopamine depletion studies including neuroimaging studies. The use of this exciting challenge technique allows us to increase our understanding of dopaminergic neurotransmission in the brain. In addition, there have been clinical reports that AMPT may be useful to treat movement disorders like dystonia, dyskinesia and Huntington's chorea, psychiatric disorders like mania, psychosis, obsessive compulsive disorder and substance abuse as well as behavioral problems in 22q11 deletion syndrome. In this review we will discuss the effects of AMPT in challenge studies that have been reported in humans. Furthermore we will review all studies reporting therapeutic effects of AMPT in neuropsychiatric disorders and adverse effects associated with AMPT use reported in both challenge and therapeutic research.

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it was reported that uncojugated bilirubin had neurotoxicity in the developing nervous system. The ‘neurodevelopmental hypothesis’ of schizophrenia was proposes that a yet-unidentified event occurring in utero or early postnatal life. We have observed that patients suffering from schizophrenia frequently present an increased unconjugated bilirubin plasma concentration when admitted to the hospital. Therefore, we had notice the relation between unconjugated bilirubin and the etiology and vulnerability of schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with GS and without GS. From the viewpoint of heterogeneity of schizophrenia, there may be poor outcome for the subtype of schizophrenia with GS.

Melatonin, a neurohormone synthesized and secreted by the pineal gland, has antioxidant, immunoregulatory and neuroprotective actions. Production of melatonin is regulated by light and darkness, light decreasing whereas darkness increasing it. Production of melatonin is also known to decline in old age and under hypoxic-ischemic conditions. Melatonin is considered as body's chronological pacemaker and has a wide array of useful applications. It has been used in the treatment of sleep disorders and is reported to have neuroprotective effects in many central nervous system (CNS) conditions such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, ischemic injury, neuropsychiatric disorders and head injury. It suppresses oxidative damage in the retina in ocular pathologies and reduces retinal ganglion cell death. It affords protection to the blood-brain and blood-retinal barriers in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. Protective effects of melatonin against hypoxic damage have been demonstrated in newborn experimental animals where it suppressed damage in many parts of the brain such as the hippocampus and choroid plexus in lateral ventricles. Along with this, exogenous administration of melatonin in newborn animals has been shown to be effective in enhancing the surface receptors and antigens on the macrophages/microglia in the CNS supporting its immunoregulatory actions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by insidious onset with cognitive impairment; affects mental function, and is of the amnesic type. Neuropathological analysis of AD-affected brains reveals extensive atrophy and an accumulation of neurofibrillary tangles. AD is a major public health issue in the ageing population and for decades, researches focused on studies using neurochemistry and biochemistry to understand the mechanisms underlying this disease. Recently, emerging evidence supports the concept that AD is also a disorder of metabolic degeneration. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing, and the possibility that the GH/IGF-I axis is involved in cognitive deficits has been recognized for several years. The IGF-I is a potent neurotrophic as well as a neuroprotective factor found in the brain, with a wide range of actions in both the central and the peripheral nervous systems. IGF-I is a critical promoter of brain development and neuronal survival, and plays a role in neuronal rescue during degenerative diseases. The investigations of GH-releasing stimulation tests, and especially of GHRH in AD, are equivocal and in some cases contradictory. After an acetylcholinesterase inhibitor, such as rivastigmine, a drug for AD, is acutely administered, the area under the curve of the GH response to GHRH doubles, showing that is a powerful drug in the enhancement of GH release. Consequently, an emerging clinical target for improving the quality of life with ageing, or for improving the clinical manifestations of AD, may be the activation of GH/IGF-I axis , which rejuvenates it, so resulting in an overall physiological benefit, with a potential for preventing or reversing detrimental age-related or AD changes in the brain.

The therapy of mood and anxiety disorders are not solved, yet, because current antidepressants have delayed onset of therapeutic action and a significant number of patients are non-responsive. Research on the field was leaning towards neuropeptides as therapeutic targets. The neurohypohyseal hormone vasopressin (VP) is a hot candidate, as beyond its peripheral actions VP is also implicated in interneuronal communication in the central nervous system and modulates behavioral functions such as feeding, learning, memory formation etc. Affective disorders are stress related disorders and for a long time, clinicians suspected a causal link between depression and the endocrine system. The most frequently occurring endocrine abnormality in depressed subjects is hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis. VP with nucleus paraventricularis hypothalami (PVN) origin is a direct adrenocorticotropin secretagogue through its V1b receptors. VP seems to have special importance under prolonged stress conditions, which are known to be strong predictive factor of depressive disorder and can induce depressive-like symptoms in animals. Moreover VP serves as neuromodulator in/between key limbic regions - amygdale, hippocampus, bed nucleus of stria terminalis and PVN. Recently an orally active V1b antagonist was also developed and seemed to have effective anxiolytic profile and its antidepressant-like effect was also demonstrated. Moreover the studies with the high anxiety Wistar rats (HAB) indicate that over-expression and - release of VP in the PVN is responsible for their depressive-like behavioral and neuroendocrine phenomena. Taken together current knowledge strongly implies an importance of vasopressinergic regulation in affective disorders and consider VP as endogenous anxiogenic/antidepressive substance.

Patients with sporadic Alzheimer's disease develop a progressive dementia in adulthood, accompanied by five main changes in the brain: loss of neurons, accumulation of intraneuronal neurofibrillary tangles and development of amyloid plaques and deposition of amyloid in neurovessels and inflammation response. Alzheimer's disease is the major form of dementia and the fourth leading cause of death in aging population. The study of neurobiology and treatment of Alzheimer's disease, now more than ever, needs an infusion of a new concept. The goals of this paper are to review knowledge of the influence amyloid and ischemic alterations on final development of Alzheimer's disease, especially with regards to the pathogenesis of Alzheimer's disease plaques, to develop a consensus on whether ischemic blood-brain barrier permeability for amyloid peptide or both are a valid target for Alzheimer's disease therapy. Alzheimer's disease today desperately needs to be treated; we can recently neither prevent nor cure it. Analyzing an experimental models of Alzheimer's disease, we will address the issue whether plaques of amyloid persist, develop with time, or both in animals injected with β-amyloid peptide. The strict reasons for this disease now are not known, but recent evidence suggests that the ischemic factors play an important role. Based on above suggestions recent direct evidence that amyloid plaques and neurofibrillary tangles can be cleared from the brain is thus provided in experimental condition. Additionally recent study provides data that immunization with β-amyloid peptide decreases blood-brain barrier permeability for β-amyloid peptide or restores blood-brain barrier integrity. This information suggests that the preventative effect of peptide aggregation, as well as the solubilization of already formed plaques by site-directed amyloid antibody is simple explanation of the removal process. Possible mechanism of action is that anti-amyloid antibodies facilitate clearance of amyloid through blood-brain barrier after plaques formation.