Serum nitric oxide metabolites in patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by myelin breakdown. The free radical nitric oxide (NO), which is considered to be a major metabolite in immune function and in autoimmune disorders, is among the possible mediators causing the inflammatory reactions in MS. Consequently, NO has been implicated in the pathogenesis of MS and its animal model experimental allergic encephalomyelitis (EAE). In this study, stable metabolites of NO (NO(2-)+NO(3-)) levels were determined in sera of MS patients (n=23) and control subjects (n=16). NO(2-)+NO(3-) levels were higher in MS patients when compared to control subjects. However, there was not any correlation with serum NO(2-)+NO(3-) values and clinical features of the disease such as duration of sickness, the time elapsed from the last attack and EDSS values. Our results imply that nitric oxide may be involved in the pathogenesis of MS although further studies are required to elucidate underlying mechanisms.

The effects of melatonin on the antioxidant systems in experimental spinal injury.

Melatonin has been recently shown by various in-vivo and in-vitro studies to exert potent neutralising effects on hydroxyl radicals, stimulate glutathione peroxidase (GSH-Px) activity, and protect catalase (CAT) from the destructive activity of hydroxyl radicals in neural tissue. We aimed to investigate the possible effects of pharmacological dose of melatonin on some of the antioxidant defence systems in an in-vivo study of experimental spinal injury. Seven groups of adult male Sprague Dawley rats were used in the following scheme: Group I: Naive (n = 6), Group II: Lesion (n = 8), Group III: Melatonin (n = 5), Group IV: Melatonin + Lesion (n = 8), Group V: Placebo + Lesion (n = 5), Group VI: Sham operation (n = 5), and Group VII: Placebo (n = 5). Experimental spinal injury was induced at level T7-T8 by 5 sec compression of the total cord with an aneurysm clip on anaesthetised and laminectomized animals. The total 10 mg/kg dose of melatonin (Sigma) dissolved in alcohol-water was administered i.p. four times in 2.5 mg/kg doses, at 20 min pre-, at the time of and at 1 h and 2h post-compression. At 24 +/- 2h post-injury, the rats were euthanized and the lesioned segments of cord were dissected and homogenised with special care taken to distribute equal amount of injured tissue in each sample for analysis of reduced glutathione (GSH), oxidised glutathione (GSSG), superoxide dismutase (SOD), and CAT activity. Compression injury decreased GSH/GSSG ratio significantly (p < .0001). Melatonin, by itself, significantly decreased GSSG content (p < .05) and increased CAT activity (p < .05) in the naïve rats. Melatonin treatment decreased GSSG activity, thus elevating GSH/GSSG ratio, and also increased SOD and CAT activity without reaching statistical significance in the lesioned animals. In conclusion, pharmacological dose of systemically applied melatonin seemed to support some features of the antioxidant defence systems in our hands.

Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic lateral sclerosis.

Abnormal glutamate metabolism is implied in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and cerebrospinal fluid (CSF) glutamate levels appear to be elevated. Since nitric oxide (NO) inhibits glutamate transport, excessive amounts of nitric oxide could underlie the glutamate induced neurotoxicity in ALS. Stable metabolites of NO (NO2- + NO3-) levels were determined in serum and CSF of sporadic ALS patients and control subjects. NO2- + NO3- levels were higher in ALS, in males and in serum samples compared to controls, females and CSF, respectively. Furthermore, while the difference between serum and CSF NO2- + NO3- levels was significant in males (higher in serum) no such difference was observed in females. Our results suggest that nitric oxide may be involved in the pathogenesis of ALS directly or indirectly and in a sexually dimorphic manner.

Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain.

Free radical damage is implicated in the course of many diseases, including age-related dementias. Oxidative deamination of primary monoamino oxidase (MAO) produces NH3 and H2O2 with established or potential toxicity. MAO activity is increased in aged rat brain and significantly lowered by chronic hydergine (codergocrine mesylate, Sandoz) treatment. The aim of this study was to investigate the effects of hydergine on enzymatic antioxidant defense systems. Hydergine or vehicle was administered systemically to young (3 months) and aged (18 months) Sprague-Dawley rats for 20 days and 24 h after the termination of the treatment, superoxide dismutase (SOD) and catalase (CAT) activities were determined in some brain regions. SOD and CAT activities were higher in the aged animals and were further increased with hydergine treatment. The increase in SOD levels caused by hydergine treatment in the aged animals were the most prominent in the hippocampus and in the corpus striatum. There was no region-specific effect of hydergine treatment on CAT levels in aged animals. The possible causal relationship between increased MAO activity, a generator of free radicals, and increased antioxidant defense in aging brain require further investigation. Decreasing MAO levels and supporting the antioxidant enzymes may underlie the efficacy of hydergine in the treatment of age related cognitive decline.

Sex differences in nitrite/nitrate levels and antioxidant defense in rat brain.

This study assessed sex differences in stable metabolites of nitric oxide and major enzymes involved in antioxidant defense in various regions of rat brain. Nitrite/nitrate levels and activities of superoxide dismutase and catalase were determined in cortex, hippocampus, corpus striatum, midbrain and cerebellum of adult male and female Sprague-Dawley rats. Nitrite/nitrate levels were significantly higher in the cortex and the hippocampus of male than female rats, while catalase activity was higher in the cortex of females than in males. These sex differences may have significant effects on brain function in health and disease.

Learning induces changes in the central cholinergic system of the rat in a sexually dimorphic pattern.

The involvement of the central cholinergic system in learning and the possible sexual dimorphism in related brain responses were investigated. Rats were exposed to different environmental conditions and to active avoidance learning. The resulting changes were studied using the following approaches: muscarinic receptor binding (MRB), acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities. The statistical evaluation of the data reveal that learning induces changes, especially in the postsynaptic component of the central cholinergic system, which shows some sexual dimorphism, and that males and females respond with different levels of increased cholinergic activity to informal and associative learning.

Naloxone binding in the frontal cortex of postmortem human brain.

1. The binding of 3H-Naloxone to opiate receptors was characterized in the frontal cortex of human post-mortem brain samples and age related changes in opiate receptors were investigated. 2. Our study revealed the presence of two binding sites with different affinities for naloxone. 3. With increasing age, the opiate receptors tend to show greater affinity for the agonistic conformation; this may imply a decline in endogenous opioid peptides with age.

Free amino acid level determinations in normal and schizophrenic brain.

1. Some disturbances in brain amino acids are reported with regard to pathological changes in schizophrenia: a reduction in GABA content and a reduced activity at some glutamatergic synapses. 2. Comparison of post-mortem brain tissue from control subjects and schizophrenic patients can provide evidence for amino acid alterations in disease. 3. The present study was undertaken to measure free amino acid concentrations in 20 brain regions obtained at autopsy, from normal persons and schizophrenics. Amino acids were extracted, esterified and separated by gas chromatography. 4. The distribution and levels of amino acids in normal persons is in accordance with similar values reported in human post-mortem brain samples by other investigators. 5. The differences in amino acids found in schizophrenic brain samples support the view of disturbed neurotransmission especially with regard to GABAergic and glutamatergic systems in schizophrenia and suggest the possible involvement of other amino acids as well.