Current Medicinal Chemistry -Central Nervous System Agents, Volume 4, No. 4, 2004
Contents
Magnesium
as a Neuroprotective Agent in Cerebral Ischemia Pp.215-222
C.C. Ionita, J.F.
Kirmani, A.R. Xavier and A.I. Qureshi
Inflammatory
Process as a Determinant Factor for the Degeneration of Substantia Nigra
Dopaminergic Neurons: Possible Relevance to the Etiology of Parkinson’s Disease Pp.223-233
M. Tomas-Camardiel,
A.J. Herrera, J.L. Venero, J.Cano and A. Machado
Oxidative/Nitrosative
Brain Damage in Stress: Possible Target for Neuropsychopharmacological Drugs Pp.235-242
Jose L.M. Madrigal,
Borja Garcia-Bueno, Antonio Cardenas, Ignacio Lizasoain, Maria A Moro, Pedro
Lorenzo and Juan C. Leza
DNA
and RNA Code-reading Molecules as Potential Gene Silencers in Neurobiology-
What are They and what are They Good for? Pp.243-253
Marcella Faria,
Carine Giovannangeli and Henning Ulrich
Selegiline
(l-Deprenyl) as a Unique Neuroprotective Agent for Chronic
Neurodegenerative Disorders- A Lesson from MAO Inhibition Pp.255-267
Ruey-Meei Wu, Dennis
L. Murphy and Chuang C. Chiueh
Cytosolic
Oligopeptidases: Features and Possible Physiopathological Roles in the Immune
and Nervous Systems
Pp.269-277
M.A.F. Hayashi,
F.C.V. Portaro, and A.C.M. Camargo
The
Hydrogen Peroxide and its Importance in Alzheimer’s and Parkinson’s Disease Pp.279-285
M. Jimenez Del Rio and C. Velez-Pardo
Abstracts
[Back to top] Magnesium as a Neuroprotective Agent in
Cerebral Ischemia
C.C. Ionita, J.F. Kirmani, A.R. Xavier and
A.I. Qureshi
In acute stroke, chemical neuroprotection is an important strategy aimed at limiting the biochemical cascade of events induced by cerebral ischemia which lead to secondary neuronal damage. Among multiple pharmaceutical interventions tried magnesium (Mg++), which is a physiological voltage-dependent N-metyl-D-aspartate (NMDA) antagonist, has demonstrated promising results. As opposed to other antiglutamate agents, Mg++ has limited adverse effects, is widely available, easy to administer, and has good penetrability in the central nervous system (CNS). Mg++ is involved in the pathogenesis of an expanding array of clinical conditions via vascular and cellular effects. Experimental stroke models and pilot clinical studies have provided encouraging data regarding the neuroprotective role of Mg++ in acute ischemic stroke. Observations from subarachnoid hemorrhage (SAH) animal models have suggested that Mg++ might have a neuroprotective effect directed against the ischemic injury which accompanies cerebral vasospasm. Large randomized, double blind clinical studies assessing Mg++ efficacy in stroke are already in progress. Magnesium sulfate is also under active investigation as a neuroprotective agent in SAH.
[Back to top]
Inflammatory Process as a
Determinant Factor for the Degeneration of Substantia Nigra Dopaminergic
Neurons: Possible Relevance to the Etiology of Parkinson’s Disease
M. Tomas-Camardiel, A.J. Herrera, J.L.
Venero, J.Cano and A. Machado
The pathological hallmark of Parkinson’s disease (PD) is a specific degeneration of dopaminergic neurons in the substantia nigra (SN). The cause of chronic nigral cell death in PD and its underlying mechanisms remain elusive. The initial degeneration of dopaminergic neurons that occurs at early stages of the disease may activate secondary phenomena, aggravating the pathological process and accounting for the continuous progression of the disease. Since 1988, when McGeer’s group showed the presence of inflammatory marks in CNS tissue of patients with PD, the substantial involvement of inflammatory events in the pathogenesis of PD has been postulated. We have developed an animal model of dopaminergic neurons degeneration by a single intranigral injection of lipopolysaccharide (LPS), an inflammatory compound. This single injection produced the induction of inflammatory process with the activation of microglia along with the specific degeneration of dopaminergic neurons in SN without effect in neither other neurotransmitter systems nor other structures of CNS. Inflammatory features have been described in models of PD, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and rotenone. Moreover, the synergic effect of inflammation on the dopaminergic degenerative process by these toxins strongly suggests the interaction between both degeneration-inducing toxins and inflammation. These evidence strongly suggest that the degenerative process could be produced by toxins, oxidative stress or bioenergetic failure along with the inflammatory process induced by these or other factors, including specific inflammatory compounds. Different inductors of inflammatory process have also been discussed in relationship to dopaminergic degeneration in the SN.
[Back to top] Oxidative/Nitrosative Brain Damage in Stress:
Possible Target for Neuropsychopharmacological Drugs
Jose L.M. Madrigal,
Borja Garcia-Bueno, Antonio Cardenas, Ignacio Lizasoain, Maria A Moro, Pedro
Lorenzo and Juan C. Leza
It has been reported that the mechanisms more directly implicated in the development and maintenance of stress-induced brain pathology in animals and humans are the high and persistent levels of glucocorticoids and excitatory amino acids. Recent findings indicate a key role for nitric oxide (NO) and the excess of pro-oxidants in various brain structures as responsible of both neuronal functional impairment (decrease in glutamate uptake, mitochondrial damage) and structural damage. Similarly, other known source of oxidants, cyclooxygenase-2 (COX-2) accounts for stress-induced brain damage. The stress-induced activation of both biochemical pathways depends on the activation of the NMDA subtype of glutamate receptor and on the activation of the transcription factor nuclear factor kB (NFkB). In the case of iNOS, the release of the cytokine TNFa also accounts for its activity. Different pharmacological strategies acting at different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNFa activation and release, inhibitors of NFkB activity, and specific inhibitors of iNOS and COX-2 activities. This article reviews the main contributions addressing a possible new pharmacological target for stress-induced neuropsychiatric disorders.
[Back to top] DNA and RNA Code-reading Molecules as
Potential Gene Silencers in Neurobiology- What are They and what are They Good
for?
Marcella Faria, Carine Giovannangeli and
Henning Ulrich
The selective silencing of a targeted gene is the ultimate goal of most strategies developed for functional studies in basic sciences and/or for drug development. Gene expression has at least three different polymeric molecules as intermediates of information processing; the gene itself, the corresponding mRNA and the polypeptide it codes for. In the present review we will focus on antigene molecules, namely triplex forming-molecules (TFMs), polyamides and designed zinc finger proteins (ZFPs) as means to achieve gene targeting, and on double-stranded RNAs (dsRNA) as means to achieve RNA interference. These two strategies are not the most frequently used, double gene knock-outs by homologous recombination tends to be preferred as antigene strategy, and antisense agents have been more extensively used when the mRNA was to be targeted. Nevertheless, some considerations regarding the specificity of antigene molecules and dsRNAs for their targets, as well as the need of relatively small and stable molecules for the triggering of selective inhibition in both cases, and no major constraints regarding the cell types they should be delivered to, emphasize their potential as gene function modulators. Pathological conditions in the nervous system can result from the malfunction of a variety of proteins, most frequently in degenerative diseases hyper stimulation or overexpression of receptors or enzymes is observed. In these particular cases, the development of efficient and specific inhibitors of gene function would be an approach of choice. Moreover, it was recently demonstrated that RNAi can be triggered in embryonic carcinoma (EC) cell lines, an accepted model for neuronal development.
[Back to top]
Selegiline (l-Deprenyl) as a Unique Neuroprotective Agent for Chronic
Neurodegenerative Disorders- A Lesson from MAO Inhibition
Ruey-Meei Wu, Dennis L. Murphy and Chuang C.
Chiueh
The purpose of this review is to describe recent advances in understanding the neuroprotective effects of selegiline (N-propanyl-l-amphetamine; l-deprenyl) and the development of a variety of novel and interesting propargyl compounds that might be potentially useful in the treatment of chronic neurodegenerative brain disorders. Selegiline is a selective, non-competitive, irreversible inhibitor of monoamine oxidase (MAO) B, and is widely used as an adjunct to L-dopa in the treatment of Parkinson's disease. Recent interest in selegiline has focused on its complex neuroprotective actions against a variety of neurotoxins, and on the pathological processes of oxidative stress and apoptosis which cause neuronal death in chronic neurodegenerative brain disorders, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. These neuroprotective effects of selegiline are due not only to MAO-B inhibition, but also to many other effects, such as suppression of free radical formation elicited by MPP+ and glutamate, up-regulation of the antioxidative enzymes, superoxide dismutase and catalase, induction of proteins interfering with the apoptotic pathway, and expression of neurotrophic factors. Recent molecular biological evidence suggests that selegiline may also alter the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other redox active molecules such as thioredoxin in brain neurons. These unique neuroprotective mechanisms of selegiline may provide models for the synthesis of new N-propargyl analogues with different structure-activity relationships, and for the development of therapeutic strategies designed to prevent the evolution of pathologic neurodegeneration.
[Back to top] Cytosolic
Oligopeptidases: Features and Possible Physiopathological Roles in the Immune
and Nervous Systems
M.A.F. Hayashi, F.C.V. Portaro, and A.C.M. Camargo
During the course of evolution, invertebrates and vertebrates have maintained common signaling molecules, such as neuropeptides that participate in a number of physiological processes. The first step of this process includes the action of prohormone convertases on the precursor proteins in order to generate the bioactive molecules. Once the neuropeptide is produced and released, it promotes the stimulation of target cells, which subsequently are desensitized to permanently maintain sensitivity to various internal or external stimuli. The desensitization process depends upon a second step in the neuropeptide metabolism that regulates its concentration in the biophase and/or controlling the stoichiometry of various peptide products. Among the putative enzymes involved in the second step of neuropeptide metabolism there are the tissue oligopeptidases: endooligopeptidase A (EOPA), endooligopeptidase B or prolyl-oligopeptidase (PO), thimet oligopeptidase (TOP) and neurolysin (NL) are the best characterized.
Recent evidences suggest that the role of the mammalian cytosolic oligopeptidases may not be restricted to their proteolytic activities. The discovery that the EOPA (also known as NUDEL) is an essential protein for the development of the CNS suggested an entirely distinct physiological role for this protein. Another oligopeptidase, the thimet oligopeptidase, was shown to be involved in the MHC class I antigen presentation, not only as a proteolytic enzyme but also as a peptide chaperone. Both activities are likely to play essential roles in the cellular immune defense. In this article we review the properties of cytosolic oligopeptidases, both as peptidases and as participants in the physiological and pathological processes of the nervous tissue and the immune defense.
[Back to top] The Hydrogen Peroxide and its Importance in
Alzheimer’s and Parkinson’s Disease
M. Jimenez Del Rio and C. Velez-Pardo
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are highly prevalent neurodegenerative disorders that cause progressive motor dysfunction, cognitive impairment, and shortened of life expectancy. Both disorders are characterized by the progressive accumulation of insoluble protein deposits such as amyloid-b plaques, tau-containing neurofibrillary tangles, a-synuclein and ubiquitin containing Lewy bodies in selected neurons in AD and PD, respectively. During the last few years, it has been established a significant percentage of patients having clinical and pathological features of both diseases. Thus, the pathological cascades of the two diseases might overlap. Based on previous in vitro and in situ studies, we propose an unified molecular cascade model wherein hydrogen peroxide (H2O2) is a paramount molecule involved in intracellular signalization that induces neuronal loss in AD and PD. This review may contribute to understand the importance of H2O2 -generated by Ab[1-42]/ Ab[25-35], a-synuclein and by either the enzymatic or metal-catalyzed oxidation of dopamine, and to highlight its implication in the design of therapeutic strategies in both diseases.