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Biomedical subjects

A C Ludolph

Publications and source records attributed to A C Ludolph.

At least 91 records · Page 5Linked to original sources
PubMed1996

Mitochondrial oxidation in rat hippocampus can be preconditioned by selective chemical inhibition of succinic dehydrogenase.

Repeatedly it was reported that a short ischemic episode may ameliorate biochemical and morphological impairment upon succeeding severe ischemia. We investigated whether the pattern of respiratory enzyme activity (RA), adenine nucleotides, and membrane potential in hippocampal slices following low-dose in vivo (20 mg/kg) and high-dose in vitro (1 mM) application of 3-nitropropionic acid (3-np), a specific inhibitor of succinic dehydrogenase (SDH), indicates a similar tolerance phenomenon. One hour in vivo treatment decreased RA, spectrophotometrically quantitated by intensity of staining with 2,3,5-triphenyltetrazolium chloride (TTC), to 48 +/- 5% (mean +/- SE; P<0.01). Intermittent increase after 2 h (79 +/- 5%; P<0.05) was followed by gradual decline to 48 +/- 16% (P<0.01) after 8 h. The intermittent increase predominated in stratum pyramidale of hippocampal region CA1 (CA1sp) vs CA3 (CA3sp) (89 +/- 6% vs 57 +/- 6% of control; P <0.01). ATP levels paralleled the intensity of average (CA1sp, CA3sp, plus CA1 stratum radiatum) TTC staining (r=0.93). After pretreatment of 3-np in vivo for 1 h, no further decrease of RA upon 30-min in vitro treatment was seen in any region. At all other times, RA declined further upon in vitro treatment (P<0.01). Compared to 1-h in vivo treatment, hyperpolarization of CA1sp pyramidal cells upon in vitro application of 1 mM 3-np was reduced after 8-h pretreatment in vivo (P<0.04). At this time, depolarization upon glibenclamide (10 muM), an antagonist at KATP-channels, was reduced. We conclude that the severity of impairment of oxidative phosphorylation upon repeated inhibition of SDH in vivo and in vitro is not increased in an additive manner. At appropriate times, relative protection against further decrease of energy metabolism is observed-chemical preconditioning. Activation of KATP-channels is associated with chemical preconditioning.

Adenine Nucleotides↗
PubMed1996

Studies of multimodal evoked potentials in treated phenylketonuria: the pattern of vulnerability.

We performed studies of multimodal evoked potentials and peripheral sensory and motor nerve conductions in 33 early and 6 late treated patients with phenylketonuria. The studies revealed the following picture: 1. In 27% of early treated patients latencies of visual evoked potentials were increased. The cause for these changes in unknown. 2. Nerve conduction studies showed the presence of a minor sensory neuropathy which in rare cases may also affect peripheral motor nerves. This neuropathy did not have features of a central-peripheral distal axonopathy which argues against a toxic/nutritional causation. 3. Deficits in the central sensory, motor, and auditory pathways were present, but rare in early treated patients. If the results of electrophysiological studies reported by different groups are compared, the emerging picture is very similar and the majority of the-minor-differences is likely to be explained by technical aspects.

Adolescent↗
PubMed1996

Toxic models of upper motor neuron disease.

Although neurotoxic models for progressive degeneration of both the anterior horn cell and the Betz cell do not exist, (neuro)lathyrism and neurocassavism (konzo) are examples of self limiting neurotoxic disorders that predominantly target the Betz cell. Both disorders are caused by the continuous intake of neurotoxic plant products (Lathyrus sativus and Manihot esculenta, respectively) which result in a virtually identical clinical picture of spastic paraparesis. A neurotoxic excitatory amino acid and AMPA agonist (beta-N-oxalylamino-1-alanine, BOAA) is held largely responsible for lathyrism. Epidemics of konzo are strongly associated with increased intake of the cyanide-liberating glycoside linamarin by protein-poor subjects. Whereas an animal model for neurocassavism does not exist, macaques fed Lathyrus sativus or BOAA develop central motor deficits with corticospinal tract involvement. Estimated dosages of Lathyrus sativus used to induce beginning lathyrism in well-nourished primates are 10-20 fold greater than those associated with irreversible human neurolathyrism. Major unexplained aspects of both diseases are the factors which allow the suspected toxins to target Betsz cells (blood-brain barrier, receptor distribution, cellular energy metabolism), the latency to onset in both diseases, and how two separate etiologic factors trigger clinically similar disorders.

Humans↗
PubMed1996

Animal models for motor neuron diseases: research directions.

Animal models of motor neuron diseases fall into three categories, hereditary (e.g., the motor neuron degenerative, wobbler, wasted, and autosomal-recessive progressive motor neuropathy mouse models), sporadically occurring (e.g., equine motor neuron disease), and experimentally induced (e.g., transgenic mice carrying a mutation in the gene encoding human Cu/Zn superoxide dismutase, toxic models) disorders. The models currently have three major drawbacks. First, there is no model imitating the progressive course of human disease with deficits of the upper and lower motor neurons. Second, experimentally induced conditions are based on a hypothesis of the pathogenetic mechanisms of human motor neuron diseases. Motor deficits are usually induced by compounds or agents that represent a single possible pathogenetic mechanism, which reduces the value of the model. Finally, the molecular biology, biochemistry, and neuropathology of the hereditary disorders are ill-defined. Future approaches should minimize the drawbacks of the current models and focus on mechanisms that are part of the etiopathogenesis of the human diseases.

Animals↗
PubMed1995

In vitro toxicological investigations of isoxazolinone amino acids of Lathyrus sativus.

Two non-protein amino acids of Lathyrus sativus, beta-(isoxazoline-5-on-2-yl)-alanine (BIA) and its higher homologue alpha-amino-gamma-(isoxazoline-5-on-2-yl)-alanine (ACI) were tested for excitotoxic potential. BIA (0.5-2.0 mM) but not ACI (2.0 mM) produced a concentration-dependent neurodegeneration in mouse cortical explants. The neuronal damage was prevented by the prior and simultaneous application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), indicating that it was mediated by non-N-methyl-D-aspartate type receptors. BIA (0.5-2.0 mM) activated CNQX-sensitive currents which were significantly smaller than those activated by 3-N-oxalyl-L-2,3-diaminopropanoic acid (beta-ODAP) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the majority of neurons. In a small number of cells, BIA (2 mM) produced currents which were similar in amplitude to those activated by beta-ODAP (50 microM). These results suggest that Lathyrus sativus plants engineered to block the synthesis of beta-ODAP may accumulate a neurotoxic precursor and therefore must be tested for the presence of both BIA and beta-ODAP.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Cu,Zn SOD in German families with ALS.

We studied the gene for Cu,Zn SOD in 15 German patients with familial ALS and did not find any mutation. Activity of the enzyme and its expression at the protein level was also normal in each patient and in 18 patients suffering from the sporadic form of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation.

Neuronal cell death during impaired energy metabolism is often attributed to increased activity at glutamate receptors, but this increase has not been directly demonstrated. We recorded responses to glutamate and N-methyl-D-aspartate in hippocampal slice CA1 neurons and glia while inhibiting mitochondrial complex II with 3-nitropropionic acid. As the period of inhibition increased, neuronal depolarization following bath application of glutamate (5 mM) or N-methyl-D-aspartate (50 microM) increased dramatically. However, depolarization upon iontophoresis of glutamate and N-methyl-D-aspartate decreased with time. A transient hyperpolarization, reflecting electrogenic sodium pump activity, was present immediately after responses to iontophoretic glutamate agonists. In the presence of the inhibitor, this hyperpolarization decreased and eventually disappeared. Even the repolarization seen upon washing of the iontophoretic or bath application of glutamate or N-methyl-D-aspartate was incomplete. Glial depolarization upon bath application of glutamate increased during inhibition, while glial depolarization upon application of N-methyl-D-aspartate decreased. Application of the N-methyl-D-aspartate antagonists aminophosphonovaleric acid (100 microM) or MK-801 (20 microM) resulted in a delay of further depolarization when applied early during the terminal decay of membrane potential following metabolic inhibition. We conclude that during impaired oxidative phosphorylation the failure of repolarizing mechanisms, not potentiated neuronal depolarization by excitants, is the primary cause of the terminal depolarization. Large glial depolarization increases the demand for neuronal ion exchange which cannot be met in situations of reduced energy metabolism. Our results provide further evidence that acute and chronic blockade of energy metabolism have different effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Toxic neuropathies and their treatment.

Peripheral neuropathy triggered by therapeutic drugs, workplace chemicals and environmental pollutants continues to be one of the most common pathological responses of the human nervous system to chemical attack. While some agents seem to damage the nerve cell directly, and a few induce primary demyelination, the large majority produces distal axonal degeneration simultaneously in long peripheral nerves and spinal tracts. Glove-and-stocking sensory loss typically precedes the development of a similar distribution of motor weakness. Clinical signs usually appear weeks after exposure has commenced; the condition continues to evolve after chemical exposure has ceased, and recovery spans a period of months or years. Careful clinical and laboratory assessment is needed to identify environmental agents responsible for human neuropathy, and reports of cases that claim a chemical causation require verification from experimental animal studies of suspect agents. Treatment of peripheral neuropathy continues to be limited, although a new therapeutic approach to patients with neuropathy-producing heavy metal intoxication is promising. Novel methods to limit nerve degeneration and promote regeneration are under study, but none has produced a convincing therapeutic effect. These are urgently needed to prevent and control the neuropathies that limit the therapeutic usefulness of drugs used in cancer chemotherapy and AIDS treatment.

Antioxidants↗
PubMed1994

Increase of ATP levels by glutamate antagonists is unrelated to neuroprotection.

Succinic dehydrogenase in mouse cortical explant cultures was inhibited by 3-nitropropionic acid (3-NPA). ATP concentrations declined upon application of 3-NPA. At 4 h, ATP levels of cultures treated with 3-NPA alone were no different from those in cultures treated additionally with MK-801 (20 microM), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) or a combination thereof. However, MK-801 and MK-801 plus CNQX mitigated morphological lesions caused by 3-NPA. CNQX alone did not influence the extent of morphological damage. In conclusion, MK-801, at concentrations which were neuroprotective against 3-NPA lesions in cortical explant cultures, did not modify 3-NPA dependent decreases in cellular ATP levels. These data indicate that the neuroprotective effects of glutamate receptor antagonists in this model are probably receptor mediated and do not involve effects on cellular metabolism.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Neurologic diseases associated with use of plant components with toxic potential.

Epidemics of neurotoxic disease in developing regions of the world are often associated with dietary dependence on plant components with inherent toxic potential or which have spoiled and become contaminated with mycotoxins. Diseases triggered by plant toxins include lathyrism and cassavism, types of irreversible spastic parapareses associated with staple diets of grass pea and bitter cassava root, respectively. Mildewed sugarcane poisoning, an encephalopathy and tardive dystonia, illustrates the neurotoxic effects of a widely distributed plant and fungal toxin. Food and medicinal use of the neurotoxic cycad plant is thought to have a role in the etiology of western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia. Plant-associated neurotoxicity is a significant and preventable cause of morbidity in certain regions of Africa, Asia, and Oceania.

Humans↗
PubMed1993

Excitotoxicity, energy metabolism and neurodegeneration.

There is increasing evidence that the neurotoxic effects of excitatory amino acids and their analogues are part of the pathogenesis of neuronal degeneration in acute and chronic neurological disease. Recent studies indicate that activation of excitatory amino acid receptors is also induced in the mechanism of neuronal damage induced by impairment of cellular energy metabolism. This article briefly summarizes the evidence for the presence of such a mechanism and discusses metabolic diseases in which excitatory amino acids alone or in combination with energy deficiency could play a pathogenetic role. In these and other metabolic diseases, antagonists to excitatory amino acid receptors may offer a therapeutic opportunity; however, there are potential limits that may prevent chronic use.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings.

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n = 8) and/or 1H spectroscopy (n = 7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6- to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200-450 ms, indicating an increase in free (extracellular) water. 1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.

Adolescent↗
PubMed1993

Studies of the etiology and pathogenesis of motor neuron diseases. III. Magnetic cortical stimulation in patients with lathyrism.

Neurophysiological assessments of central motor pathways were conducted of 11 Spanish subjects with varying degrees of spastic paraparesis (lathyrism). The disease has been induced more than 40 years ago by subsistance on the neurotixic chick pea Lathyrus sativus. Patient evolution was carried out by magnetic cortical and electric spinal stimulations and recordings of the contralateral muscle responses. Central motor conduction times corresponding to lower limbs were clearly more prolonged in those severely affected patients with marked difficulty walking (Stages 4 and 3). Central conduction times corresponding to upper limbs were delayed in only 1 patient. Taken together with clinical and published neuropathological data, these findings suggest that established lathyrism is essentially a central motor system disorder primarily affecting corticospinal tracts regulating the lower limbs.

Age of Onset↗