Current
Drug Targets-CNS & Neurological Disorders, Volume 2, No. 2, 2003
Contents
Pharmacological
Findings Contribute to the Understanding of the Main Physiological Mechanisms
of Memory Retrieval Pp. 81-94
Daniela M. Barros, Luciana A. Izquierdo, Jorge H. Medina
and Ivan Izquierdo
Biochemical
and Therapeutic Effects of Antioxidants in the Treatment of Alzheimer’s
Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis Pp. 95-107
Vincenzo Di Matteo and Ennio Esposito
Emerging
Signalling and Protein Interactions Mediated Via Metabotropic Glutamate
Receptors Pp. 109-122
Randal X. Moldrich and Philip M. Beart
Mechanism
of Action of Volatile Anesthetics: Involvement of Intracellular Calcium
Signaling Pp. 123-129
Renato S. Gomez and Cristina Guatimosim
Use
of Diffusion- and Perfusion-Weighted Magnetic Resonance Imaging in Drug
Development for Ischemic Stroke Pp. 131-141
Turgut Tatlisumak and Fuhai Li
3,4-Dihydroxyphenylacetaldehyde:
A Potential Target for Neuroprotective Therapy in Parkinson’s Disease Pp.
143-148
W.J. Burke
[Back to top] Pharmacological
Findings Contribute to the Understanding of the Main Physiological Mechanisms
of Memory Retrieval
Recent pharmacological findings have shown that retrieval of one-trial avoidance learning requires glutamate receptors, cAMP-dependent protein kinase and mitogen-activated protein kinases in the hippocampus, entorhinal, posterior parietal and anterior cingulate cortex. It requires AMPA but not other type of glutamate receptors or the protein kinases in the amygdala. Retrieval is modulated by dopamine D1, ß-noradrenergic, serotonin 1A and cholinergic receptors in the four cortical structures mentioned, and by ßnoradrenergic receptors in the basolateral amygdala. Further, retrieval is also modulated by peripheral ACTH, glucocorticoids, vasopressin, ß-endorphin and catecholamines; these hormones probably act through ß-noradrenergic receptor systems in the basolateral amygdala. Exposure to novelty or the systemic administration of antidepressant drugs prior to retention tests enhances retrieval, even for very remote memories. The effect of novelty is mediated by molecular mechanisms similar to those of retrieval itself.
[Back to top] Biochemical and
Therapeutic Effects of Antioxidants in the Treatment of Alzheimer’s Disease,
Parkinson’s Disease, and Amyotrophic Lateral Sclerosis
Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading
to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Morever, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.
[Back to top]
Emerging Signalling and Protein Interactions Mediated Via Metabotropic
Glutamate Receptors
Metabotropic glutamate receptors (mGlu) are GTP-binding (G) protein-coupled receptors (GPCRs) that are involved in learning and memory, cardiovascular control and motor function. Their structure and pharmacology has been reviewed recently in Current Drug Targets: CNS and Neurological Disorders (Vol. 1, Issue 3) where their roles in a variety of neurological disorders were highlighted. The present review focuses on the emerging evidence for interactions of mGlu receptors with other GPCRs in the CNS at the membrane interface and amongst signaling cascades in the cytosol (e.g. intracellular Ca2+, cAMP and scaffolding proteins). While initially non-selective activity was thought to be responsible for many atypical responses, increasing evidence points to GPCR interactions in neurons and glia, with adrenoceptors, adenosine receptors, dopamine receptors and muscarinic receptors. For example, group II mGlu receptors were found to be required for group I mGlu receptor induction of long-term potentiation at the postsynaptic terminal. Increasing evidence demonstrates the intimate interaction of adenosine receptors and mGlu receptors, particularly in the regulation of neurotransmitter release. While adenosine itself can be released from astrocytes by co-activation of group II mGlu and β-adrenergic receptors. Given the complexity of neurological disorders such as ischemic stroke, Alzheimer’s disease and epilepsy, exploitation mGlu receptor-associated GPCR interactions may prove efficacious in the treatment of such disorders.
[Back to top] Mechanism of
Action of Volatile Anesthetics: Involvement of Intracellular Calcium Signaling
There have been extensive efforts to characterize the mechanism of action of volatile anesthetics, but their molecular and cellular actions are still a matter of debate. Volatile anesthetics act primarily on synaptic transmission in the central nervous system but proof of this as the predominant mechanism of action remains elusive. Changes in neurotransmitter release may relate to direct interaction of the anesthetic molecule with an ion channel protein or synaptic protein, but can also be a consequence of alterations in intracellular signaling. Calcium is one of the most important messengers in cells and its intracellular concentration may be modified by several agents including volatile anesthetics. Neuronal excitability is in part determined by calcium availability that is controlled by several mechanisms. Because voltage-gated calcium channels (VGCC) play a key role in controlling Ca2+ entry and in initiating cellular responses to stimulation through an elevation of intracellular calcium concentration ([Ca2+]i), they are thought to be one of the targets for volatile anesthetics. However, [Ca2+]i can also be altered without the participation of VGCC through receptor-mediated pathways. Indeed, calcium homeostasis is also controlled by plasma membrane Ca2+-adenosine triphosphatase, sarcoplasmic-endoplasmic reticular Ca2+-ATPase, the Na+-Ca2+ exchanger, and mitochondrial Ca2 + sequestration. Alteration of any of those mechanisms that control [Ca2+]i may lead to a change in presynaptic transmission or postsynaptic excitability. Here we will review some of the recent progress in identifying putative actions of volatile anesthetics, specifically the effect on intracellular calcium homeostasis in neurons.
[Back to top] Use
of Diffusion- and Perfusion-Weighted
Magnetic Resonance Imaging in Drug Development for Ischemic Stroke
Diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI, respectively) are novel imaging modalities that can detect brain ischemia early in its full extent, can be performed in minutes, can be repeated easily, and allow for follow-up of the ischemic lesion size over time with good spatial and temporal resolution. We have used DWI and PWI in evaluating novel therapeutic approaches for ischemic stroke in numerous studies in the rat and lately in humans. It is now clear that DWI and PWI offer a good combination for safe and reliable evaluation of novel drugs on the size and tissue characteristics of brain ischemia. After inducing focal brain ischemia in the rat, one can first detect the presence and extent of ischemia by DWI and hypoperfusion by PWI, calculate the volume of ischemic brain tissue, and then follow the development of the ischemic lesion over time for several hours during treatment, thus detecting in vivo effects of the novel drug on brain ischemia. Successful reperfusion (either mechanically or as a result of thrombolytic therapy) can also be detected easily. DWI and PWI when performed before starting treatment can also exclude the pretreatment bias, a potential reason for false-positive studies in which proper imaging studies are not employed. Thus we can determine the in vivo efficacy (or lack of efficacy) of new therapeutic regimens (both neuroprotective and thrombolytic) rapidly, safely, and reliably by using a small sample size only, and adapt the same strategy to clinical trials.
[Back to top] 3,4-Dihydroxyphenylacetaldehyde:
A Potential Target for Neuroprotective Therapy in Parkinson’s Disease
The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson’s disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for á-synuclein (á-syn). Investigations implicate a DA metabolite as mediator of á-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (•OH) trigger aggregation of á-syn to its toxic form. DOPAL with H2O2 generates •OH radicals.
These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q10 increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington’s disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of á-syn should limit DOPAL toxicity.