Central Nervous System Agents in Medicinal Chemistry

ISSN: 1871-5249

Central Nervous System Agents in Medicinal Chemistry
Volume 6, Number 4, December 2006

Contents


Glioma Therapy: A Novel Insight in the Immunotherapeutic Regime with T11TS/SLFA-3 Pp. 245-270
Swapna Chaudhuri and Anirban Ghosh
[Abstract]


Alzheimer Disease: What Role for Leptin and Insulin? Pp. 271-279
Sami Dridi, D. Dominguez and J. Buyse
[Abstract]


Induced Adaptive Resistance to Nitrooxidative Stress in the CNS: Therapeutic Implications Pp. 281-291
Amy Bishop, Renea Gooch and James Anderson
[Abstract]


Depression Under the Perspective of Oxytocin Pp. 293-310
Angelica Rosat Consiglio
[Abstract]


Peripheral and Central Mechanisms of Mechanical Allodynia: Neurokinin Receptor for Therapeutic Target Pp. 311-320
Mamoru Takeda and Shigeji Matsumoto
[Abstract]




Abstracts


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Glioma Therapy: A Novel Insight in the Immunotherapeutic Regime with T11TS/SLFA-3
Swapna Chaudhuri and Anirban Ghosh

Brain tumors of glial origin i.e. glioma are most difficult neoplasm to treat with modern therapeutic interventions viz. surgery, radio- and chemotherapies. Therefore, a continuous search is ‘on’ for the alternative modalities of treatment particularly with different immunomolecular therapeutic regimes. Use of restorative and adaptive immunotherapies with different BRMs, cytokines, tumor vaccines, site directed therapies with molecular blocking agents are now practiced to combat with glioma and still no major breakthrough has been obtained to extend life expectancy significantly. In our laboratory a novel immunotherapeutic probe i.e. T11TS/SLFA3, a membrane glycoprotein of sheep erythrocyte, with its activities of glioma killing in experimental animals has been attempted. With the fundamental details of neuroimmune components, particularly the resident microglia and brain infiltrating lymphocytes, the modulation of their activities by T11TS was evidenced. The activation of microglia, infiltration of lymphocytes, enhanced performance of effector functions and regulation of the cytokine network with T11TS in the brain compartment superseding the glioma induced immune suppression, is the major achievement found with T11TS mediated immunotherapy. These immune effector functions are culminated into the clearance of glioma, which is clearly depicted by the study of apoptosis and cell cycle analysis. This molecule with the carnage of glioma differentially regulates the population of microglia and lymphocytes in brain to regain homeostasis by modulating intrinsic cellular protein levels. Additionally, when this glycoprotein is used for toxi-cological evaluation, it showed mearly no adverse effects on animals, rather health promotion. Therefore, this glycoprotein T11TS potentially provides an effective immunotherapeutic option against glioma with the potentials of new drug development.


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Alzheimer Disease: What Role for Leptin and Insulin?
Sami Dridi, D. Dominguez and J. Buyse

Among neurodegenerative diseases, Alzheimer disease (AD) is a leading cause of death in elderly individuals. AD is characterized, among other clinical findings, by unexplained weight loss, cachexia and altered immune function. Alteration in energy balance and nutritional status are relayed to the feeding-related hypothalamic nuclei by neuronal pathways and/or via alterations in the levels of eating-controlling hormones. The adipocyte-derived hormone, leptin, and the pancreatic-derived peptide, insulin, function as hormonal signaling mechanisms for fat deposition and play a key role in regulating food intake, body weight and energy homeostasis via their actions on specific hypothalamic nuclei. Moreover, leptin, insulin and their receptors are widely expressed in many hypothalamic and extra-hypothalamic brain regions indicating that these hormones may have other neuronal functions. Although emerging evidence supports the role of insulin resistance in the development of AD, the potential involvement of leptin in the pathogenic process of AD has been proposed only recently. Here we review recent reports and progress concerning the molecular mechanism and the potential role of leptin and insulin in AD.


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Induced Adaptive Resistance to Nitrooxidative Stress in the CNS: Therapeutic Implications
Amy Bishop, Renea Gooch and James Anderson

NO is a free radical that is normally released and utilized by the CNS for a variety of normal physiological functions such as neurotransmission and differentiation. However, if NO released in inappropriate locations, in excess or at a high flux rate, it is toxic. In the CNS, after injury or during disease, NO is released by astrocytes, activated microglia, or macrophages that have migrated across the blood-brain barrier, and is concomitant with massive cell death. Nitrotyrosine formation, a marker for NO-mediated damage, is seen in CNS injury and in many neurodegenerative diseases such as Alzheimer’s, ALS, multiple sclerosis and spinal injury. In our lab we have found that motor neurons pretreated with sub-toxic doses of NO gain resistance to normally toxic doses of NO. This phenomenon, induced adaptive resistance (IAR), is demonstrated by a significant decrease in the percentage of apoptotic cells in response to a toxic dose of NO. IAR is dependent on the heme-metabolizing enzyme, heme oxygenase-1 (HO1), as indicated by 1) an increase in HO1 expression, 2) loss of resistance in CNS cells incubated with HO1 inhibitors, and 3) lack of native NO resistance in cells isolated from spinal cords of HO1-null mice. The overall aim of this review is to elucidate and dissect the IAR phenomenon and the HO1 signal transduction axis on which it depends, and by so doing, begin to understand native resistance mechanisms in the CNS that can be manipulated to protect neurons against NO-mediated damage seen in CNS injury and neurodegenerative disease.


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Depression Under the Perspective of Oxytocin
Angelica Rosat Consiglio

Stress may lead animal and human behavior to an unstable condition in short and long term. It is a risk factor to a mental disorder such as depression, which is generally related to a failure after an effort. Its high prevalence is worldwide and it is a WHO (World Health Organization) concern. Depression may impair social, economical and affective relationships, besides bringing great suffering to the human being. The main symptoms are decreased energy and motivation, anhedonia, sadness, difficulty for concentration and memory, bonding disruptions, etc. The most accepted hypothesis for depression can be well recognized by the main drugs currently adopted for its treatment: they include serotonin and noradrenaline as their fundamental basis. However, their efficacies are still limited.

A promising candidate that might help modulate this disease is oxytocin (OT). OT is a nonapeptide produced by the hypothalamus which exerts central and peripheral effects, not only during pregnancy and lactation, but acts in male and non pregnant females as well. It is being considered as an antistress neuropeptide and it has antidepressive effects. However, the blood brain barrier greatly impairs peripheral OT to reach the brain.

The general goal of this review is to raise some issues concerning advantages and difficulties related to a possible exogenous administration of OT for this mental disorder. More specifically, it will be reviewed: 1. stimuli for OT release (behavioral/endocrinological and chemical/drugs); 2. OT effects on the central nervous system, mainly related to stress; 3. exogenous OT: routes of administration, blood brain barrier, indirect mechanisms of action, whole molecule x fragments of OT, doses.

This review will not cover all aspects of the multifactorial disorder such as depression into all its variables. However, it may contribute to the understanding of one possible component, the oxytocinergic system.


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Peripheral and Central Mechanisms of Mechanical Allodynia: Neurokinin Receptor for Therapeutic Target
Mamoru Takeda and Shigeji Matsumoto

It is well known that many patients complain about sensory abnormalities involving chronic pain. Mechanical allodynia is defined as pain caused by stimuli that do not normally evoke pain and that which is mediated by low-threshold mechanoreceptive Aβ-fibers. Understanding of the peripheral and central mechanisms of the mechanical allodynia has been perceived as follows: 1) increased excitability of peripheral and central terminals and their cell bodies, including local paracrine mechanisms; 2) The reduction in inhibition (disinhibition) in the spinal cord (i.e. the decreased inhibitory activity of GABA/glycinergic interneurons; 3) The reorganization of synaptic connections in the spinal dorsal horn (Aβ-afferents sprout into the superficial layer). A suspected possible interaction between noxious and non-noxious sensory signal transmission pathways may play to a key role in the induction of mechanical allodynia. Conversely, substance P is one member of the tachykinin families as well as an important neurotransmitter in nociceptive (Aδ-/C-) primary afferent neurons. Its effect is known to bind primarily to the neurokinin 1 receptor. More recent studies have suggested that mechanical allodynia and their related neuronal responses can be attenuated by pretreatment with a specific neurokinin 1 receptor blocker. Therefore, in this review, we introduce our recent data and discuss the possible interaction between mechanical allodynia and the neurokinin 1 receptor as it pertains to use in therapeutic applications.