Superior orbital 'petrositis' and late ischaemic monocular blindness induced by intense UV radiation exposure.

Many physical agents cause neuropathies. The most common are chronic pressure, vibration and temperature. In general, these lesions occur at work, as a result of accidents or through chronic exposure to the physical agent. Radiation leading to peripheral neuropathy is also related to radiotherapy in cancer treatment, as an undesirable side-effect. We present here a case report of short, intense UV radiation exposure at work, leading to delayed-onset ocular neuropathy. A clear cause-effect relationship is shown, demonstrated using magnetic resonance imaging scans. We suggest that the mechanism was thermal and ischaemic.

Chemiluminescent aldehyde and beta-diketone reactions promoted by peroxynitrite.

Peroxynitrite is shown here to promote the aerobic oxidation of isobutanal (IBAL) and 3-methyl-2,4-pentanedione (MP) in a pH 7.2 phosphate buffer into acetone plus formate and biacetyl plus acetate, respectively. These products are expected from dioxetane intermediates, whose thermolysis is known to be chemiluminescent (CL). Accordingly, the extent of total oxygen uptake by IBAL at different concentrations parallels the corresponding CL maximum intensities. The pH profile based on oxygen uptake data for the MP reaction matches the titration curve of peroxynitrous acid (pK(a) approximately 7), indicating that peroxynitrite anion is the oxidizing agent. Energy transfer studies with IBAL and the 9, 10-dibromoanthracene-2-sulfonate ion, a triplet carbonyl detector, indicates that triplet acetone (tau = 19 micros) is the energy donor. It is postulated that IBAL- or MP-generated triplet carbonyls are produced by the thermolysis of dioxetane intermediates, which are formed by the cyclization of alpha-hydroperoxide intermediates produced by insertion of dioxygen into the IBAL or MP enolyl radicals, followed by their reduction. Accordingly, EPR spin-trapping studies with 3,5-dibromo-4-nitrosobenzenesulfonic acid (DBNBS) and 2-methyl-2-nitrosopropane (MNP) revealed the intermediacy of carbon-centered radicals, as expected for one-electron abstraction from the enol forms of IBAL or MP by peroxynitrite. The EPR data obtained with IBAL also reveal formation of the isopropyl radical produced by competitive nucleophilic addition of ONOO(-) to IBAL, followed by homolytic cleavage of this adduct and beta-scission of the resulting Me(2)CHCH(O(-))O(*). Superstoichiometric formation of fragmentation products from IBAL or MP attests to the prevalence of an autoxidation chain reaction, here proposed to be initiated by one-electron abstraction by ONOO(-) from the substrate. This work reveals the potential role of peroxynitrite as a generator of electronically excited species that may contribute to deleterious and pathological processes associated with excessive nitric oxide and aldehyde production.

Neuroleptic drug-stimulated iron uptake by synaptosome preparations of rat cerebral cortex.

Neuroleptic-induced tardive dyskinesia has been linked to impaired iron homeostasis in the central nervous system attributed to increased iron levels. A chlorpromazine stimulatory effect upon iron uptake from 55Fe-citrate and 55Fe-transferrin by cortical synaptosome preparations of rats was recently demonstrated. The present work extends this study to other neuroleptic drugs such as thioridazine, haloperidol, clozapine and fluphenazine. Like chlorpromazine, thioridazine showed a stimulatory effect upon iron uptake from both iron donors whereas fluphenazine highly increased uptake from 55Fe-citrate but not from 55Fe-transferrin. Haloperidol and clozapine had no effect. Stimulation of iron uptake by neuroleptics is probably related to their property of calmodulin antagonism, since calmidazolium also stimulated synaptosomal iron uptake from both donors. Calmidazolium-stimulated uptake from 55Fe-citrate was approx. 5-fold when compared to control samples while uptake from 55Fe-transferrin was 250% higher. The results are in agreement with the iron uptake magnitude observed with the different drugs for the two iron donors used and the reported Ki values of neuroleptic drugs for calmodulin antagonism evaluated by the inhibition of 3',5'-monophosphate phosphodiesterase activity. Moreover, vanadate, an inhibitor of protein phosphorylation and KCl-promoted membrane depolarization, greatly inhibited iron uptake from 55Fe-citrate by both chlorpromazine-treated and untreated synaptosome preparations.

delta-Aminolevulinic acid-induced synaptosomal Ca2+ uptake and mitochondrial permeabilization.

delta-Aminolevulinic acid (ALA) overload is thought to be responsible for the neuropsychiatric manifestations of various porphyric disorders. In fact, ALA-generated oxyradicals have been shown to cause oxidative lesions in rat brain synaptic membranes and to decrease GABAergic receptor affinity. We now describe a stimulatory effect of ALA (1 mM) on Ca2+ uptake by cortical synaptosomes and an inhibitory effect on both transmembrane potential and oxygen consumption of intrasynaptosomal mitochondria. Both effects were partly abolished by the addition of antioxidants and the mitochondrial transmembrane potential dissipation observed to be protected by 1 microM ruthenium red. Based on these data and on the synaptosomal 14C-ALA uptake capacity, we suggest that ALA causes oxidative damage to the mitochondrial membrane. These ALA properties might be involved in the neuropsychiatric porphyric manifestations since enhanced cellular Ca2+ uptake and cerebral mitochondria dysfunction seem to be associated with several neurodegenerative processes.

The prooxidant effect of 5-aminolevulinic acid in the brain tissue of rats: implications in neuropsychiatric manifestations in porphyrias.

5-Aminolevulinic acid (ALA), a heme precursor accumulated during the clinical expression of acute intermittent porphyria, lead poisoning, and tyrosinosis, has been hypothesized to act as an endogenous source of oxyradicals. We now report oxidative effects on brain tissue of rats submitted to ALA treatment. Upon acute treatment (40 mg/kg body weight) increased total nonheme iron in the cortex (20%) was observed. After prolonged ALA administration (40 mg/kg body weight on alternate days during 2 weeks), the following indicators of oxidative stress were found to be significantly increased: CuZnSOD activity (67%) in total brain homogenate, total iron (68%) and ferritin (71%) in the cortex, ferritin in striatum (44%), protein carbonyls in homogenate of cerebral cortex (threefold) and 45Ca2+ uptake by cortical synaptosomes (45%). In addition, synaptic membranes prepared from whole brain assayed with the radioligand 3H-muscimol, revealed increased Kd values (twofold) of the high-affinity GABAergic receptor binding and formation of protein carbonyl groups, thiobarbituric acid reactive products, and conjugated dienes. In vitro, ALA produced similar effects upon the high affinity 3H-muscimol binding. No apparent alteration of either dopaminergic or serotonergic [3H]-ligand binding was observed. These results argue in favor of ALA-triggered oxidative stress in brain accompanied by iron metabolism alterations and GABAergic receptor damage, which may be implicated in the neuropsychiatric manifestations of the aforementioned porphyrias.