Central Nervous System Agents in Medicinal Chemistry

ISSN: 1871-5249

Central Nervous System Agents in Medicinal Chemistry
Volume 8, Number 3, September 2008

Contents

Antibodies As Promising Novel Neuroprotective Agents in the Central Nervous System Injuries Pp. 143-169
Hari Shanker Sharma and Aruna Sharma
[Abstract]


Glutamate-Based Drugs for the Treatment of Clinical Depression Pp. 170-176
J.R. Leheste, C. Curcio, L. Baldinger, S. Sarwar, S.M. Zakhary, B.H. Hallas, J.M. Horowitz and G. Torres
[Abstract]


Postischemic-Anoxic Encephalopathy After Global Forebrain Ischemia Pp. 177-186
Baowan Lin
[Abstract]


Glycogen Metabolism and Brain Pathologies Pp. 187-197
Jean-François Cloix, Marie-Yvonne Ardourel and Tobias Hévor
[Abstract]


Adult Neurogenesis and Drug Therapy Pp. 198-202
P. Taupin
[Abstract]


Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds Pp. 203-219
John P. Frampton, Michael L. Shuler, William Shain and Matthew R. Hynd
[Abstract]




Abstracts


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Antibodies As Promising Novel Neuroprotective Agents in the Central Nervous System Injuries
Hari Shanker Sharma and Aruna Sharma

Injury to the central nervous system (CNS) initiates a series of complex events that are responsible for cell and tissue damage over time. The primary insult, i.e., trauma, ischemia, hypoxia, hyperthermia, etc., results in secondary injury cascades involving release of several neurochemicals and other factors that alters the brain micro-fluid environment. The most important secondary injury events include increased levels of cytokines, e.g., Tumor Necrosis Factor-alpha (TNF-α ), and production of nitric oxide (NO) causing direct damages to cell membranes, disrupting the blood-brain barrier (BBB) function and brain edema formation. Apart from these factors, several other neurochemical mediators of the BBB and brain edema formation, i.e., serotonin, prostaglandin, histamine, glutamate, dynorphin, etc., contribute to cell and tissue injuries. Importantly, an interaction among these mediators plays prominent roles in the development of brain pathology. It appears that some of the endogenously released substances have neuroprotective ability, whereas the other elements are injurious to the CNS indicating that a balance between endogenous neurodestructive and neuroprotective factors is crucial for the cell injury or survival. Thus, using highly selective and specific antibodies raised against possible neurodestructive elements is likely to neutralize their effects in vivo and results in neuroprotection. This review deals with neuroprotective effects of antibodies directed against serotonin, dynorphin, TNF-α and nitric oxide synthase in animal models of CNS trauma and hyperthermic brain injury. Studies carried out in our laboratory since last 2 decades show that topical or intracerebroventriculalry administered antibodies against neurodestructive factors attenuate trauma or hyperthermia induced BBB dysfunction, brain edema formation and cell damage. These novel observations indicate a promising role of antibodies as therapy in CNS injuries to induce neuroprotection. The possible mechanisms and functional significance of antibodies induced neuroprotection is discussed.


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Glutamate-Based Drugs for the Treatment of Clinical Depression
J.R. Leheste, C. Curcio, L. Baldinger, S. Sarwar, S.M. Zakhary, B.H. Hallas, J.M. Horowitz and G. Torres

Clinical depression is a chronic, recurrent mood disorder that causes significant disability and disease burden throughout the world. Not surprisingly, there is an enormous demand for finding (a) appropriate medications and devices for treating the clinical symptoms and (b) the underlying molecular mechanisms of the disease. Currently, most therapeutic treatments of depression indirectly target the serotonin and norepinephrine systems of the brain, as these neurotransmitters have long been considered promising and mechanistically relevant to the etiology of mood disorders. However, selective serotonin reuptake inhibitors such as sertraline, fluoxetine and paroxetine do not always substantially improve clinical outcome, and when they do show efficacy, it takes weeks of treatment to achieve an appreciable clinical effect. These observations suggest that a serotonin and norepinephrine hypothesis of depression is incomplete at best, and that novel, rapid onset therapeutic options for depression must be considered. In this review, we highlight several potential new drugs for clinical depression based on recent discoveries about the neurotransmitter glutamate and its family of receptors. Moreover, we discuss the possibility that glutamate-based antidepressant drugs might affect covalent histone modifications including acetylation in areas of the brain (e.g., pre-frontal cortex, hippocampus) thought to be relevant for the pathogenesis of affective disorders. If so, histone hyperacetylation and thus chromatin remodeling might be important regulatory mechanisms underlying the effects of ketamine and other N-Methyl-D-Aspartate receptor antagonist drugs. Chromatin remodeling may represent a non-serotonin/norepinephrine therapeutic strategy for treatment of clinical depression, a strategy that may also be appropriate in the context of drug discovery and drug development.


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Postischemic-Anoxic Encephalopathy After Global Forebrain Ischemia
Baowan Lin

Postischemic-anoxic encephalopathy, defined as delayed progressive secondary injury occurs in humans after resuscitation following cardiac arrest. It is much more severe than the initial episode of global brain ischemia from heart attack. This encephalopathy is widespread and may happen after heart surgeries and hypoxia owing to acute carbon monoxide intoxication. About 30%-80% of survivors of resuscitation undergo further brain deterioration, characterized by dementia, Parkinson’s syndrome and/or paralysis associated with parenchymal lesions, which may emerge in the days following initial recovery from the acute ischemia. The encephalopathy contains 2 types of injury: 1) macro- and microinfarcts or confluent areas of pan-necrosis with consequent neuronal loss and astroglial activation, 2) perivascular and diffuse tissue sponginess without gliosis. Beta-amyloid protein (Aβ) deposition is found in these patients’ brains. Experiments reveal that histopathological changes occurring in animals are similar to those in humans. The vicious circle is made of by endothelial injury + platelet aggregation → thrombosis → infarction → endothelial injury and platelet aggregation → thrombosis → circulation decline → infarction. The secondary circulation declines cause the encephalopathy. Endothelial injury and platelet aggregation induce micro- and macro-infarction. Platelet activity and broken blood-brain barrier (BBB) contribute to part of the Aβ deposition. Cerebral Aβ accumulation induces neuronal shrinkage and disap-pearance, and may lead to perivascular rarefaction. Cyclooxygenase-2 (COX2) might be involved in the ischemic injury. A combination of protecting endothelia, inhibiting platelet aggregation and activity, and inhibiting COX2 is key to reducing secondary infarction and preventing neurodegeneration, and thus, to alleviate the encephalopathy.


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Glycogen Metabolism and Brain Pathologies
Jean-François Cloix, Marie-Yvonne Ardourel and Tobias Hévor

Glucose is the main fuel for cell life, and supports a number of different processes in providing cells with energy. Excess glucose is polymerized into glycogen, which is an energy-glucose store. Alterations in glycogen content and/or synthesis have been reported in human neuropathologies, such as Alzheimer’s disease, epilepsies and cancer.

Epileptic foci are hypometabolic during the interictal period, and probably hypermetabolic during crisis. Animal models of epilepsies are used for studying the reasons why neurons suddenly and temporally synchronize their activity. One model associates seizures of the “grand mal” type with cortical glycogen accumulation: induction of epileptiform crisis by methionine sulfoximine (MSO). The glycogen accumulation, observed in astrocytes only, occurs as soon as the pre-convulsive period. High glycogen has also been demonstrated in primary cultures of astrocytes.

Abnormal glycogen content has been characterized in various types of cancers, including gliomas. High invasion properties, spontaneous resistance to chemotherapeutic drugs, and a mean prognosis of 12 months characterize glioblastomas, the highest grade of gliomas that inevitably leads to death. The various therapeutic means, including surgery, chemical and radio-therapies, and gene therapy have thus far been inefficient in significantly improving patient survival. Glycogen synthesis was targeted in cell lines from murine and human glioblastomas by an antisense glycogen synthase cDNA strategy; and the inhibition of glycogen synthesis in these cell lines decreases both in vitro and in vivo invasiveness.

Glycogen can therefore be considered as putatively involved in at least two different pathologies of the brain, such as epilepsies and cancer. This abnormal glycogen content and synthesis can be proposed as putative diagnostic and therapeutic targets in brain pathologies.


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Adult Neurogenesis and Drug Therapy
P. Taupin

Current drug therapy strategies for the nervous system are based on the assumption that the adult central nervous system (CNS) lacks the capacity to make new nerve cells and regenerate after injury. Contrary to a long-held dogma, adult neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult CNS. Neurogenesis in the adult brain is modulated in a broad range of environmental conditions, and physio- and pathological processes, as well as by trophic factors and drugs. This suggests that newborn neuronal cells of the adult brain may be involved in the functioning of the nervous system and may mediate a broad range of physio and pathological processes, as well as the activities endogenous and exogenous factors and molecules. Hence, the confirmation that adult neurogenesis occurs in the adult brain and NSCs reside in the adult CNS force us to rethink how drugs are functioning and whether their activity may be mediated through adult neurogenesis. This will lead to the development and design of new strategies to treat neurological diseases and injuries, particularly drug therapy.


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Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds
John P. Frampton, Michael L. Shuler, William Shain and Matthew R. Hynd

Cell culture models can provide information pertaining to the effective dose, toxiciology, and kinetics, for a variety of neuroactive compounds. However, many in vitro models fail to adequately predict how such compounds will perform in a living organism. At the systems level, interactions between organs can dramatically affect the properties of a compound by alteration of its biological activity or by elimination of it from the body. At the tissue level, interaction between cell types can alter the transport properties of a particular compound, or can buffer its effects on target cells by uptake, processing, or changes in chemical signaling between cells. In any given tissue, cells exist in a three-dimensional environment bounded on all sides by other cells and components of the extracellular matrix, providing kinetics that are dramatically different from the kinetics in traditional two-dimensional cell culture systems. Cell culture analogs are currently being developed to better model the complex transport and processing that occur prior to drug uptake in the CNS, and to predict blood-brain barrier permeability. These approaches utilize microfluidics, hydrogel matrices, and a variety of cell types (including lung epithelial cells, hepatocytes, adipocytes, glial cells, and neurons) to more accurately model drug transport and biological activity. Similar strategies are also being used to control both the spatial and temporal release of therapeutic compounds for targeted treatment of CNS disease.