Biomedical subjects

M Gerlach

Publications and source records attributed to M Gerlach.

At least 73 records · Page 4Linked to original sources

PubMed2000

Is there neuroprotection in Parkinson syndrome?

Parkinson's disease (PD) is a neurodegenerative disorder of the aging population with unknown etiopathogenesis. It is assumed that the underlying pathobiochemical processes comprise multifactorial and multigenetic disturbances leading to a progressive and devastating disorder without remission. Subtypes exist suggesting that "PD" is a spectrum disorder with variations in the cascade of pathobiochemical and genetic events. Neuroprotective endogenous processes are lost at the very beginning of PD. Supplementation of substances with neuroprotective and/or neurorescue capacity is eminent for future therapeutic strategies. MAO-B inhibitors, NMDA-receptor antagonists and dopamine receptor agonists fulfill such a criterion in preclinical studies while there is no clear evidence for clinical neuroprotection. However, PET-controlled studies comparing L-DOPA-treated and ropinirol-treated PD patients give evidence for the "concept of neuroprotective treatment strategies".

Dopamine Agonists↗

PubMed2000

Altered redox state of platelet coenzyme Q10 in Parkinson's disease.

BACKGROUND: The reduced form of coenzyme Q10 (CoQ10) acts as a lipophilic antioxidant and participates in electron and proton transport of the respiratory chain in the inner mitochondrial membrane. An alteration in CoQ10 redox state may thus reflect a change in membrane electron transport and the effectiveness of defense against toxic reactive oxygen species such as hydrogen peroxide and superoxide. In Parkinson's disease alterations in the activities of complex I have been reported in substantia nigra and platelets. Deficiency of mitochondrial enzyme activities could affect electron transport which might be reflected by the platelet CoQ10 redox state. METHOD: We have determined concentrations of the reduced and oxidized forms of CoQ10 and the activity of monoamine oxidase B in platelets isolated from parkinsonian patients and age- and gender-matched controls. RESULTS: Platelet CoQ10 redox ratios (reduced CoQ10 to oxidized CoQ10) and the ratio of the reduced form, compared with total platelet CoQ10, were significantly decreased in de novo parkinsonian patients. Platelet CoQ10 redox ratios were further decreased by L-DOPA treatment (not significant), whilst selegiline treatment partially restored CoQ10 redox ratios. Monoamine oxidase activities in non-selegiline treated patients were similar to controls. INTERPRETATION: Our results either suggest an impairment of electron transport or a higher need for reduced forms of CoQ10 in the platelets of even de novo parkinsonian patients. However, the CoQ10 redox ratio was not correlated to disease severity, as determined by the Hoehn and Yahr PD disability classification, suggesting that this parameter may not be useful as a peripheral trait marker for the severity of PD but as an early state marker of PD.

Aged↗

PubMed2000

Cerebral oligaemia episode triggers free radical formation and late cognitive deficiencies.

Sixty minutes of cerebral oligaemic hypoxia, induced by bilateral clamping of the carotid arteries (BCCA) in pentobarbital-anaesthetized normotensive rats, induces a late progressive cognitive decline when compared with sham-operated controls. Analysis at BCCA of hippocampal metabolism using microdialysis showed increased release of glutamate, aspartate and gamma-aminobutyric acid, followed by a progressive rise in the formation of hydroxyl free radicals measured as 2,3-dihydroxybenzoic acid (2,3-DHBA), their reaction product with salicylate, though only in the re-perfusion phase. In the striatum increased dopamine release occurred during BCCA, whereas glutamate and aspartate showed an increase only during the late re-perfusion phase. gamma-Aminobutyric acid (GABA) concentration increased during BCCA and early re-perfusion. An increase in 2,3-DHBA was seen during BCCA, and persisted over 2 h of re-perfusion. Six and 13 months after surgery, though not as early as 3 months, BCCA-treated rats perform worse than sham-operated controls in a water-maze, where decreased swimming speed reveals striatal dysfunction, while hippocampal dysfunction manifested as diminished spatial bias. These results show that cerebral oligaemia, similarly to cerebral ischaemia, leads to increased extracellular dopamine, aspartate and glutamate, and the production of hydroxyl radicals in structures associated with learning and memory processes. Unlike cerebral ischaemia, in cerebral oligaemia the appearance of spatial memory deficits is delayed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins.

Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.

Adult↗

PubMed2000

The serotonin transporter in Alzheimer's and Parkinson's disease.

The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.

Alleles↗

PubMed1999

BCR-ABL and v-SRC tyrosine kinase oncoproteins support normal erythroid development in erythropoietin receptor-deficient progenitor cells.

Erythropoietin (Epo)-independent differentiation of erythroid progenitors is a major characteristic of myeloproliferative disorders, including chronic myeloid leukemia. Epo receptor (EpoR) signaling is crucial for normal erythroid development, as evidenced by the properties of Epo(-/-) and EpoR(-/-) mice, which contain a normal number of fetal liver erythroid progenitors but die in utero from a severe anemia attributable to the absence of red cell maturation. Here we show that two constitutively active cytoplasmic protein tyrosine kinases, P210(BCR-ABL) and v-SRC, can functionally replace the EpoR and support full proliferation, differentiation, and maturation of fetal liver erythroid progenitors from EpoR(-/-) mice. These protein tyrosine kinases can also partially complement the myeloid growth factors IL-3, IL-6, and Steel factor, which are normally required in addition to Epo for erythroid development. Additionally, BCR-ABL mutants that lack residues necessary for transformation of fibroblasts or bone marrow cells can fully support normal erythroid development. These results demonstrate that activated tyrosine kinase oncoproteins implicated in tumorigenesis and human leukemia can functionally complement for cytokine receptor signaling pathways to support normal erythropoiesis in EpoR-deficient cells. Moreover, terminal differentiation of erythroid cells requires generic signals provided by activated protein tyrosine kinases and does not require a specific signal unique to a cytokine receptor.

Animals↗

PubMed1999

Characterization and regional distribution of nitric oxide synthase in the human brain during normal ageing.

Nitric oxide (NO) is a highly diffusible cellular mediator generated from L-arginine by the enzyme nitric oxide synthase (NOS). As little is known about the regional distribution of NOS in the human brain, we examined the distribution pattern of nitric oxide synthase activity in 28 regions of the human brain using the [(3)H]L-citrulline formation assay. To elucidate which isoforms contribute to the total NOS activity we performed Western blot analysis of neuronal, inducible and endothelial NOS. We further determined brain levels of arginine and citrulline as a potential index of NOS activity pre mortem. NOS activity appears to remain unaltered during ageing and is independent of post mortem delay, gender or sample storage time. We identified a regional pattern of NOS distribution with highest levels of NOS activity in the substantia innominata, cerebellar cortex, nucleus accumbens and subthalamicus, whereas lowest levels were measured in the corpus callosum, thalamus, occipital cortex, and dentate nucleus. nNOS was measured throughout the brain, in contrast iNOS and eNOS were not detectable. We therefore conclude that primarily nNOS is responsible for NOS activity in the human brain. Levels of citrulline were higher than those of arginine, but did not correlate with the enzyme activity, suggesting that these parameters are unsuitable for testing NOS activity premortem. The characterization and topographical pattern of NOS in the human brain during normal ageing may assist our understanding of the physiological role of NO and its relevance in Parkinson's and Alzheimer's disease, alcoholism, schizophrenia and AIDS.

Adolescent↗

PubMed1999

Involvement of microglia in cerebrospinal fluid glutamate increase in SIV-infected rhesus monkeys (Macaca mulatta).

Cerebrospinal fluid (CSF) samples were collected from 24 uninfected and 24 SIV251 MPBMC-infected rhesus monkeys during early infection and from 6 animals in a longitudinal design up to 7 months postinfection to investigate excitatory and inhibitory amino acid neurotransmitter levels. During the early infection period CSF amino acid concentrations of infected animals were not significantly different from those of uninfected animals. However, long-term studies demonstrated that gamma-aminobutyric acid (GABA) concentrations were decreased while glutamate concentrations were increased late in infection compared with the preinfection values of the same animals. Moreover, we showed that the source of increased glutamate in animals with AIDS is, at least partially, microglial cells. Our data support the hypothesis that excitotoxicity is involved in immunodeficiency virus-induced neurological disease and propose microglia as a contributor to excitotoxic damage.

Animals↗

PubMed1999

Parkinson's disease: a major hypokinetic basal ganglia disorder.

Disorders of the basal ganglia can be broadly divided into two: ones that manifest hypokinesia or those that elicit hyperkinesia. Parkinson's disease is the commonest form of hypokinetic disorder. The term Parkinson's disease (PD) usually encompasses idiopathic and Parkinsonian-like syndromes. PD is a chronic and progressive disease, in which the symptoms tend to appear unilateral to begin with. Subsequently subtle dysfunctions on the contralateral side may also be observed. Tremor, akinesia and rigidity are some of the classical features of the disease. Although many hypotheses have been proposed, the cause of PD largely remains obscure. Management of PD includes pharmacological treatment or/and surgical intervention.

Animals↗

PubMed1999

Exhaled nitric oxide in patients with Wegener's granulomatosis.

In Wegener's granulomatosis (WG), a pathogenic role of infections, in particular of a chronic colonization of the nasal mucosa with Staphylococcus aureus, has been postulated. Nitric oxide (NO), which is thought to play a role in primary host defence and inflammation, is produced endogenously within the respiratory tract, mainly from the paranasal sinuses. In order to further characterize its role in WG, nasal and pulmonary NO excretion in WG patients in comparison to healthy volunteers was measured. Seventeen patients with WG were included in the study. Five patients had active disease (bloody rhinitis with ulceration and crusting) and immunosuppressive therapy (IST), and 12 were in remission (six with, and six without, IST). S. aureus was found in the swabs of all patients with active WG and in three patients in remission. NO was measured in exhaled gas using a chemiluminescence analyser. The NO excretion rate in nasally sampled gas was significantly reduced (p<0.05) in patients with active WG ((mean+/-SD)102+/-100 nL x min(-1)) compared to healthy controls (299+/-13 nL x min(-1)), and patients in remission (281+/-86 nL x min(-1) with IST, 280+/-133 nL x min(-1) without IST). Pulmonary NO excretion in active or nonactive WG patients did not significantly differ from that of healthy volunteers (48+/-21 nL x min(-1)). These results demonstrate a reduced nasal NO excretion in active Wegener's granulomatosis. This may be caused by destruction and/or functional impairment of sinus epithelium. The reduced NO concentration may well compromise host defence in the upper airways, thus contributing to colonization with Staphylococcus aureus and further promoting Wegener's granulomatosis.

Adult↗

PubMed1999

Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library.

Advanced glycation end products (AGEs) contribute to changes in protein conformation, loss of function, and irreversible crosslinking. Using a library of dipeptides on cellulose membranes (SPOT library), we have developed an approach to systematically assay the relative reactivities of amino acid side chains and the N-terminal amino group to sugars and protein-AGEs. The sugars react preferentially with cysteine or tryptophan when both the alpha-amino group and the side chains are free. In peptides with blocked N-terminus and free side chains, cysteine, lysine, and histidine were preferred. Crosslinking of protein-AGEs to dipeptides with free side chains and blocked N termini occurred preferentially to arginine and tryptophan. Dipeptide SPOT libraries are excellent tools for comparing individual reactivities of amino acids for nonenzymatic modifications, and could be extended to other chemically reactive molecules.

Amino Acid Sequence↗

PubMed1999

Nitric oxide diffusion across membrane lungs protects platelets during simulated extracorporeal circulation.

BACKGROUND: The absence of a protective endothelial surface on membrane oxygenators during extracorporeal circulation (ECC) promotes platelet trapping and damage, leading to increased bleeding complications. We investigated the effects of transmembranous diffusion of gaseous nitric oxide (NO) on platelets during simulated ECC. MATERIAL AND METHODS: Two paired circuits were run in parallel with fresh, heparinized (1 U mL-1) blood from healthy human donors for 240 min. To one of the paired circuits, 20 ppm NO was added transmembranously. RESULTS: NO significantly attenuated platelet trapping and reduced intracircuit platelet activation evaluated by the release of beta-thromboglobulin, platelet factor 4 and soluble P-selectin. Furthermore, NO significantly preserved platelet reactivity to stimulating agents (ADP and adrenaline), evaluated as the ability to expose P-selectins and activate glycoprotein (GP)-IIb-IIIa. Nevertheless, circulating activated platelets expressing P-selectin or activated GPIIb-IIIa were not different and were not significantly increased. The mean fluorescence intensity of GPIb and GPIIb-IIIa decreased in both circuits equally. CONCLUSIONS: Transmembranous diffusion of gaseous NO revealed protective effects on platelets by reducing thrombocytopenia/pathia and preserving platelet reactivity.

Adenosine Diphosphate↗

PubMed1999

L-selectin in trauma patients: a marker for organ dysfunction and outcome?

BACKGROUND: Systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) are important factors affecting morbidity and mortality after trauma. Adhesion molecules, e.g. L-selectin (CD62 L), play crucial roles in both conditions. PATIENTS AND METHODS: In 51 multiple trauma patients, CD62 L surface expression on granulocytes, monocytes, lymphocytes, as well as sCD62 L plasma concentrations were determined during the first 6 days after trauma, starting at the site of accident. Clinical parameters were severity of injury scores (ISS, APACHE II), requirement of red blood cell transfusion, acute lung or liver failure, development of MODS or SIRS, early (< or = 6 d) or late (> 6 d), and outcome. RESULTS: CD62 L expression was reversibly elevated on granulocytes, T cells and monocytes in comparison with initial values. sCD62 L plasma concentrations did not show temporal variations but were depressed throughout observation period, in comparison with healthy controls. Lung failure within the first 6 days was associated with increased CD62 L expression on monocytes and B cells on admission and increased sCD62 L concentrations after 12 and 24 h. Patients with more severe injuries (APACHE II > 20 points) had higher sCD62 L concentrations after 24 h. Non-survivors had decreased sCD62 L (on admission) and T-cell CD62 L expression (after 4 h). Patients with early MODS or SIRS showed increased monocyte CD62 L expression after 6 days. CONCLUSIONS: In multiple trauma patients, severe organ dysfunction is associated with altered CD62 L expression on leukocytes and circulating sCD62 L plasma concentrations. However, the obvious complexity of the pattern currently restricts use of CD62 L quantitation for clinical purposes.

Adolescent↗

PubMed1999

Effects of Selegiline in a retroviral rat model for neurodegenerative disease.

Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-inflammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which--under different conditions--exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) significantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

Animals↗

PubMed1999