Showing papers on "Neurodegeneration published in 1991"

Iron‐Melanin Interaction and Lipid Peroxidation: Implications for Parkinson's Disease

Abstract: The vulnerability of substantia nigral (SN) melaninized dopamine neurons to neurodegeneration in Parkinson's disease and the selective increases of iron and basal lipid peroxidation in SN indicate that iron-melanin interaction could be crucial to the pathogenesis of this disease. The present study describes, for the first time, the identification and characterization of a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding site for iron on dopamine melanin. The binding of iron to melanin is dependent on pH and the concentration of melanin. Iron chelators, U74500A, desferrioxamine, and to less extent 1,10-phenanthroline and chlorpromazine, but not the Parkinson-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can inhibit the binding of iron to melanin and iron-induced lipid peroxidation. Although melanin alone diminishes basal lipid peroxidation in rat cortical homogenates, it can also potentiate that initiated by iron, a reaction inhibited by desferrioxamine. In the absence of an identifiable exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in pars compacta of SN may be a strong candidate for the cytotoxic component of oxygen radical-induced neurodegeneration of melaninized dopamine neurons.

Aminooxyacetic acid results in excitotoxin lesions by a novel indirect mechanism.

Abstract: Aminooxyacetic acid (AOAA) is an inhibitor of several pyridoxal phosphate-depedent enzymes in the brain. In the present experiments intrastriatal injections of AOAA produced dose-dependent excitotoxic lesions. The lesions were dependent on a pyridoxal phosphate mechanisms because pyridoxine blocked them. The lesions were blocked by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and by coinjection of kynurenate, a result indicating an NMDA receptor-mediated excitotoxic process. Electrophysiologic studies showed that AOAA does not directly activate ligand-gated ion channels in cultured cortical or striatal neurons. Pentobarbital anesthesia attenuated the lesions. AOAA injections resulted in significant increases in lactate content and depletions of ATP levels. AOAA striatal lesions closely resemble Huntington's disease both neurochemically and histologically because they show striking sparing of NADPH-diaphorase and large neurons within the lesioned area. AOAA produces excitotoxic lesions by a novel indirect mechanism, which appears to be due to impairment of intracellular energy metabolism, secondary to its ability to block the mitochondrial malate-aspartate shunt. These results raise the possibility that a regional impairment of intracellular energy metabolism may secondarily result in excitotoxic neuronal death in chronic neurodegenerative illnesses, such as Huntington's disease.

Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons.

Abstract: Considerable evidence suggests that altered neuronal calcium homeostasis plays a role in the neuronal degeneration that occurs in an array of neurological disorders. A reduction in microtubules, the accumulation of 8–15 nm straight filaments, and altered antigenicity toward antibodies to the microtubule-associated protein tau and ubiquitin, as well as granulovacuolar degeneration, are observed in many human neurodegenerative disorders. Progress toward understanding how and why human neurons degenerate has been hindered by the inability to examine living human neurons under controlled conditions. We used cultured human fetal cerebral cortical neurons to examine ultrastructural and antigenic changes resulting from elevations in intracellular calcium levels. Elevation of intracellular calcium by exposure to a calcium ionophore or a reduced level of extracellular Na+ for periods of hours to days caused a loss of microtubules, an increase in 8–15 nm straight filaments, and increased immunostaining with Alz-50 and 5E2 (tau antibodies) and ubiquitin antibodies. Granulovacuolar degeneration was also observed. Antigenic changes in tau were sensitive to phosphatases, and the electrophoretic mobility of tau was altered in cells exposed to calcium ionophore, indicating that tau was excessively phosphorylated as the result of elevated intracellular calcium levels. Colchicine also caused an accumulation of straight filaments and altered tau immunoreactivity, suggesting that a disruption of microtubules secondary to altered calcium homeostasis may be a key event leading to altered tau disposition and neuronal degeneration. These data demonstrate that aberrant rises in intraneuronal calcium levels can result in changes in the neuronal cytoskeleton similar to those seen in neurodegenerative disorders, and suggest that this experimental system will be useful in furthering our understanding of the cellular and molecular mechanisms of human neurological disorders.

Altered Protein Tyrosine Phosphorylation in Alzheimer's Disease

Abstract: The activity of protein tyrosine kinase was determined in extracts from Alzheimer's disease brains and age- and postmortem time-matched control brains at autopsy using the synthetic peptide substrate poly(Glu4Tyr1). The specific activity of protein tyrosine kinases in the particulate fraction decreased roughly twofold (p less than 0.02) in Alzheimer's disease frontal cortex relative to unaffected control cortex. Cytosolic protein tyrosine kinase activity in Alzheimer's disease tissue was not significantly different from that in control tissue. In contrast to reduced particulate protein tyrosine kinase activity, analysis of Western blots of cytosolic and particulate fractions revealed increases in cytosolic antiphosphotyrosine immunoreactive polypeptides with molecular masses of 55 and 60 kDa. Quantitative immunohistochemistry and morphometry of frontal cortex sections with the antiphosphotyrosine antibody indicated increased antiphosphotyrosine staining in the neurons, although the number of antiphosphotyrosine-positive neurons per square millimeter decreased. Also, increased antiphosphotyrosine staining was observed in the hippocampal neurons. These results suggest that altered protein tyrosine kinases and protein tyrosine phosphorylation are involved in the pathology of Alzheimer's disease.

Quinolinic acid and kynurenic acid in the mammalian brain.

Abstract: Over the last decade, the study of neuroexcitatory amino acids has become one of the most rapidly expanding areas of neuroscientific research. Interest in this class of compounds was precipitated mainly by the realization that metabolites such as glutamate and aspartate are major neurotransmitters in the central nervous system (Fonnum, 1984; Erecinska and Silver, 1990). However, it is now clear that excitatory amino acids not only play a significant role in a wide array of brain processes such as synaptic plasticity and motor control but may also, as “excitotoxins”, be causally involved in the pathogenesis of various neuro-psychiatric diseases (Cavalheiro et al., 1988). Thus, the pathological overstimulation of excitatory amino acid receptors situated in the neuronal membrane is now believed to result in neurodegeneration in cerebral hypoxia/ischemia, temporal lobe epilepsy and several other diseases including chronic neurodegenerative disorders such as Huntington’s disease (HD) (Schwarcz et al., 1984; Schwarcz and Meldrum, 1985; Rothman and Olney, 1986; Choi, 1988). Pharmacological probes have been used to subdivide the receptors which mediate excitotoxic insults. These receptor are linked to ion channels and are named after their model agonists N-methyl-D-aspartate (NMDA), kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) (Watkins et al., 1990).

NMDA-Receptor Antagonist Prevents Measles Virus-induced Neurodegeneration.

Abstract: N-methyl-d-aspartate (NMDA) receptors represent a major subtype of excitatory amino acid receptors in the mammalian brain. In addition to their physiological role, NMDA receptors have been linked to the occurrence of nerve cell death in several neurodegenerataive diseases. The hamster neurotropic (HNT) strain of measles virus causes non-inflammatory encephalopathy in mice. This is associated with neuronal loss in areas CA1 and CA3 of the hippocampus. Systemic treatment with the non-competitive NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate (MK-801) prevented this cellular necrosis. Thus, a virus may have indirect neurodegenerative effects in the brain due to activation of NMDA receptors.

Death of cultured hippocampal pyramidal neurons induced by pathological activation of N-methyl-D-aspartate receptors is reduced by monosialogangliosides.

Abstract: Glutamate-induced delayed neurotoxicity has been proposed to account for the selective loss of hippocampal pyramidal neurons after an ischemic period. We have studied the effects of exogenous glutamate and combined oxygen-glucose deprivation on the survival of hippocampal pyramidal neurons cultured from rat fetuses. Acute glutamate neurotoxicity (20 min, 23-25 degrees C) occurred in a concentration-dependent manner (LD50: 50 microM), destroying virtually all neurons 24 hr later. Such injury was prevented by N-methyl-D-aspartate (NMDA), but not non-NMDA, antagonists. Hippocampal cell death induced by removal of oxygen and glucose showed a similar pharmacological profile, indicating a role for NMDA receptor activation in neuronal loss associated with this energy crisis situation. Monosialogangliosides such as GM1 were effective in protecting against neurodegeneration induced by either direct glutamate exposure or oxygen and glucose deprivation. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation may provide a new therapeutic tool for excitatory amino acid-related brain injury processes.

Nutrition, neurotoxicants and age-related neurodegeneration.

Abstract: The National Institute on Aging supports a program of investigation of "biomarkers" of aging (biological parameters that change in magnitude with age), some of which may be among the, as yet unknown, causes of Alzheimer's disease. Exposure to neurotoxicants can also produce symptoms similar to Alzheimer's disease and has been proposed as a causative factor. We have examined the role of dietary factors and age on Alzheimer's disease-like neurohistological and behavioral symptoms as well as on the neurochemical effects of treatment with a prototypical neurotoxicant, trimethyltin (TMT). We found that aging greatly increased the susceptibility of hippocampal neurons to TMT-induced neurodegeneration. Limiting the dietary intake of calories, which has been reported to slow the aging process, also reduced the neurotoxic effects of a given dose of TMT. Our current research focuses on the use of neurotoxins to model neurodegenerative conditions of aging in animals. We propose that by identifying an age-amplified biomarker or biomarkers somewhere along the chain from neurotoxic stimulus to neuronal necrosis we may also discover an up- or down-regulated gene, via it's gene product, that contributes to the etiology of human dementias. Our preliminary data suggest that up-regulated synthesis of post-synaptic glutamate receptors of the kainic acid-preferring subtype may be such a biomarker.

Acetyl-L-carnitine: a drug able to slow the progress of Alzheimer's disease?

Abstract: Defects in cholinergic neurotransmission do not, by themselves, constitute the sole pathophysiologic concomitants of Alzheimer's disease (AD). Recent findings point out that abnormalities in membrane phospholipid turnover and in brain energy metabolism may also characterize AD. Acetyl-L-carnitine (ALC) is an endogenous substance that, acting as an energy carrier at the mitochondrial level, controls the availability of acetyl-L-CoA. ALC has a variety of pharmacologic properties that exhibit restorative or even protective actions against aging processes and neurodegeneration. A review of a series of controlled clinical studies suggests that ALC may also slow the natural course of AD.

A calcium-channel antagonist can prevent paramyxovirus-induced neurodegeneration.

Abstract: Mumps virus caused a partially lytic infection in cultivated rat embryonic dorsal root ganglion neurons with a restricted formation of viral components. The neuronal degeneration was markedly enhanced by increasing the calcium concentration of the medium and could be almost totally inhibited by the dihydropyridine calcium channel antagonist nifedipine. The drug had no effect on a productive and completely lytic Sendai virus infection of the neurons. A previous neurophysiological study has shown that a reduced calcium influx occurs during the action potential early during the infection. The present study suggests a crucial role of calcium in neurodegeneration induced by certain viruses.

Subcortical Changes Following Ischaemic and Other Lesions of Cerebral Cortical Structures: Trophic Mechanisms and Neuronal Degeneration

Abstract: Clinical signs of dementia are generally accompanied by abnormal organic changes in the brain, including neuronal degeneration in specific cortical and subcortical regions. The processes leading to neuronal degeneration in dementia are not well understood, and the relative importance of degenerative dysfunction in cortical versus subcortical neuronal systems in giving rise to dementia is still unclear. Dementia may be caused by neurodegeneration of different origins, as in Alzheimer’s disease or ischaemic dementia, but the affected neurons may have characteristics that make them vulnerable to common features of different insults. For example, although Azheimer’s disease and ischaemic dementia might superficially seem quite different, both involve cortical structures that are uniquely rich in excitatory amino acid receptors, and excitotoxicity mediated by amino acid transmitters has been suggested to play a role in the neuronal cell death seen in both conditions [11,25]. Basic research that leads to a better understanding of neurodegenerative processes will form an important part of developing effective therapeutic strategies for dementia. In this context, experimental animal models constitute an important means of studying both the mechanisms underlying degenerative events, and their subsequent behavioural consequences.

Methamphetamine and MPTP: Similarities and Differences in Mechanisms of Neurotoxic Action

Abstract: The primary pathophysiological finding in the brains of those afflicted with Parkinson's Disease (PD) is an extensive loss of nigrostriatal dopaminergic neurons within the basal ganglia. Although considerable research has focused on the elucidation of the cause for this neurodegeneration, the substance or mechanism responsible for this neurodegeneration is unknown. A Parkinsonian syndrome can occur in individuals who are exposed acutely to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Ballard et al., 1985) or to those exposed chronically to manganese (e.g. manganese miners; see Barbeau, 1984). The symptoms seen in those patients who have ingested toxic quantities of MPTP are nearly identical to those seen in idiopathic PD whereas those seen in humans who have been exposed chronically to high levels of manganese are somewhat different than those in idiopathic PD and may reflect damage not only to nigrostriatal dopaminergic but to other neuronal systems as well. These findings have led to two different hypotheses regarding the etiology of PD. One is that a compound similar in structure or biochemical characteristics to MPTP, derived from exogenous or endogenous sources, is responsible for the neurodegeneration of nigrostriatal dopaminergic neurons in PD. Another is that the oxidation of DA results in the formation of oxygen-derived reactive species (quinones and/or superoxide or the hydroxyl radical) capable of cytotoxicity as is believed to occur in Mn2+ poisoning.

Comparison of Ca 2 ÷ -activated proteinase enzyme and endogeneous inhibitor activity in brain tissue from normal and Alzhekrner's disease cases

Abstract: Summary Recent evidence has suggested that Alzheimer's disease may result from an underlying defect of protein catabolism. In an attemp~ to identify such a defect, we have determined the levels of Ca 2 + -activated proteinase (principally calpain [I) and endogeneous inhibitor (calpastatin) activity in normal and Alzheimer's disease cases, following fractionation of parietal cortex lgrey and white matter) via anion-exchange chromatography. The chromatographic elution profiles and levels of calpain II activity were found to be similar in grey and white matter in both normal and Alzheimer's disease cases. The characteristics of calpain II, ineluding Ca :~ concentration required for optimum activity for enzymes partially purified from normal or Alzheimer's disease cortex were identical. Similarly, the chromatographic elution profiles and levels of total calpastatin activity (approximately equal to that for calpain II activity) were found to be similar in grey and white matter from normal and Alzheimer's disease cases. These data suggest that the characteristic neurodegeneration associated with Alzheimer's disease does not result from alteration in the level of activity or characteristics of the calpain/catpastatin system in the cerebral cortex of patients with this disorder.