Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. 783 34

Transplantation of whole pancreas or pancreatic islets remains a promising approach to treatment of diabetes mellitus. Since there is no efficient method presently known for in vivo detection of pancreatic islet rejection, we have utilized dithizone [DTZ] to monitor the survival of transplanted islet allografts following the induction of tolerance by a new strategy of deliberate introduction of donor antigens into the adult thymus. In this study, we examined the morphology of islet allografts in vivo and in vitro following pretreatment with intrathymic (IT) inoculation of 2 mg soluble Ag obtained from 3M KCl extracts of resting T-cells with or without ALS immunosuppression in the WF-to-Lewis combination. Fresh isolated rat islets stained pink 3-5 minutes following exposure to medium containing 0.12 mM DTZ solution in DMSO. Intravenous (i.v.) injection of DTZ solution into unmodified recipients of islet allografts that had rejected their grafts showed massive degranulation of islets which did not stain pink with DTZ. This was confirmed by microscopic finding of fibrosis and lymphocytic infiltration. In contrast, i.v. injection of DTZ solution into long-term recipients of islet allografts at 50, 100, and 150 days after transplantation showed viable islet cells which stained crimson red with DTZ and the findings were confirmed with microscopic sections. This study demonstrates that DTZ is an effective means of in vivo and in vitro identification of transplanted pancreatic islets and suggests that this strategy may have potential clinical application in the diagnosis of the pancreatic islet rejection.
 ...
PMID:Monitoring of rat islet allografts with dithizone after induction of donor specific transplant tolerance by intrathymic administration of soluble alloantigens. 1037 Jul 99

It is shown that exposure of 365 nm UV radiation at doses of 10, 20 and 50 kJ/m2 induces a dose-dependent increase in DNA single-strand breaks and alkali-labile sites (SSB and ALS) detected by comet and halo assays in human blood lymphocyte nucleoids. Adding 10% dimethyl sulfoxide (DMSO) reduces the SSB and ALS yields--in 3 times. A strong drop in the output of UV-A-induced SSB and ALS in lymphocyte nucleoids in the presence of DMSO shows the leading role of *OH radicals in this DNA damage formation under exposure to 365-nm UV-radiation.
 ...
PMID:[Effect of dimethyl sulfoxide on the extent of DNA single-strand breaks and alkali-labile sites induced by 365 nm UV-radiation in human blood lymphocyte nucleoids]. 2576 18

Microneurotrophins (MNT's) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT's retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT's offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate. MNT's cross artificial membranes mimicking the blood-brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes. A lead MNT (BNN27) and its mono-oxidation metabolites enter mouse brain rapidly. RNA-sequencing measured gene expression profiles of human H9eSC-(embryonic stem cell)-derived or CTL (control) subject iPSC-(induced pluripotential stem cell)-derived MN's exposed to NT proteins or MNT molecules. Expression ratios (relative to DMSO (dimethylsulfoxide) vehicle) were calculated, and the resulting top 500 gene lists were analyzed for Gene Ontology (GO) grouping using DAVID (Database for Annotation, Visualization and Integrated Discovery). The MNT's BNN20, BNN23, and BNN27 showed overlap of GO terms with NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) in the H9eSC-derived MN's. In the iPSC-derived MN's two (BNN20, BNN27) showed overlap of GO terms with NGF or BDNF. Each NT protein had GO terms that did not overlap with any MNT in the MN cell lines.
...
PMID:Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis. 2749 23