Sergio Algeri

A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes

Aging is a major risk factor for neurodegenerative diseases including Alzheimers disease (AD), Parkinsons disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. An increasing number of studies show that nutritional antioxidants (especially Vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor-kappaB (NF-kappaB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kappaB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.

Changes in monamines and their metabolite levels in some brain regions of aged rats

The concentrations of dopamine (DA) norepinephrine (NE), serotonin (5HT) and their metabolites, HVA, DOPAC, MHPG-SO4 and 5HIAA were measured in several brain areas of rats aged 4, 18 and 29 months. Dopamine and its metabolites showed a decline, statistically correlated with age, in all the dopaminergic areas considered, indicating that this system is profoundly affected in the senescent rat. The changes in the noradrenergic system were more complex. This neurotransmitter was reduced in spinal cord and in limbic area, but was not modified in hippocampus, cerebellum, striatum and s. nigra. In cortex, MHPG-SO4, the main NE metabolite, showed a significantly age-related increase. Tyrosine hydroxylase (TH) activity was low in striatum, and brainstem but not in hypothalamus of aged rats. Neither 5HT nor its metabolites was affected by age. The results indicate that central catecholaminergic systems are markedly affected in senescent rats.

Age-related modification of dopaminergic and β-adrenergic receptor system: Restoration to normal activity by modifying membrane fluidity with s-adenosylmethionine

Microviscosity of membranes prepared from striata and cortex of 3 or 30-month-old rats was measured by fluorescence polarization and electron spin resonance. The viscosity of the hydrophobic core of the lipid bilayer was significantly increased in striatal but not in cortical membranes of old rats. In old rats the incorporation of methyl groups into phosphatidylcholine was significantly lower than in young rats. beta-Adrenergic specific binding sites were reduced in striata, cortex and pineal gland of old rats. In the striata of these animals, [3H] spiperone specific binding sites and dopamine-stimulated adenylate cyclase were also low. A chronic treatment of old rats with S-adenosyl-L-methionine, the cofactor in phospholipid methylation, lowered microviscosity to normal values in striata but not in the cortex. In the same old rats, the beta-receptor in striata and pineal gland returned towards juvenile values; in the cortex, the modification was in the same direction but did not reach significance. Neither putative dopaminergic receptors nor the adenylate cyclase age-dependent decrease was modified by treatment with S-adenosyl-L-methionine.

Significance of dopamine metabolites in the evaluation of drugs acting on dopaminergic neurones

The effect of various drugs was studied on 3-methoxytyramine (3-MT) concentrations in rat striatum. The drugs were chosen for their ability to interfere with the dopaminergic system at different levels. Dopamine (DA) acidic metabolites, i.e. homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), were also measured. Changes of 3-MT, unlike those of DOPAC and HVA, seem to reflect the functional activity of dopaminergic neurons. In fact drugs believed to increase or decrease DA content in the synaptic cleft produce predictable changes of striatal 3-MT. Thus cocaine, nomifensine and d-amphetamine increase 3-MT concentrations while gamma-butyrolactone, alpha-methyltyrosine and apomorphine decrease it.

Tetrahydropapaveroline: formation in vivo and in vitro in rat brain.

Abstract Gas chromatographic-mass spectrometric techniques have been used for the measurement of tetrahydropapaveroline (THP) from brain. The formation of THP from 1-DOPA or dopamine in vitro has been confirmed by obtaining a complete mass spectrum of the product as its trifluoroacetylated derivative. Following chronic administration of 1-DOPA or 1-DOPA in combination with ethanol to rats, THP formed in vivo in in brain could be detected in small quantities although it could not be detected when ethanol alone was administered.

Catecholamine synthesis in brain of ageing rat

SEVERAL lines of evidence indicate that in mammals there is a progressive deterioration of central nervous system function with ageing (BOWERS & GERBODE, 1968; BRIZZEE et al., 1975; DHOPESHWARKAR & MEAD, 1975 ; SCHEIBEL & SCHEIBEL, 1975). Many neurophysiological processes such as motor activity, thermoregulation, sleep and hormonal secretion do in fact deteriorate in old animals (FINCH et al., 1969; GOODRICK,

Effect of Life-Long Hypocaloric Diet on Age-Related Changes in Motor and Cognitive Behavior in a Rat Population

Aged (24 months), adult (12 months), and young (4 months) rats kept on standard or hypocaloric diets from the age of three weeks old were tested in a range of behavioral tests to determine the effects of aging on sensory-motor and cognitive behavior and to assess whether such effects were prevented by life-long calorie restriction. An age-related deterioration of sensory-motor functions, motility and exploratory activity was observed in all the senescent animals independent of diet. Swimming ability did not deteriorate with age. Spatial memory, evaluated by the Morris water maze test, showed some deterioration in normally fed adult rats as indicated by the deceleration in the learning curve. In aged rats, not only was learning slowed down, but memory utilization was also impaired. These cognitive deficiencies were absent in rats fed the hypocaloric diet.

Behavioral and biochemical changes monitored in two inbred strains of mice during exploration of an unfamiliar environment

Mice of the C57BL/6 (C57) and DBA/2 (DBA) strains were introduced individually in an unfamiliar environment (a large cage where food, water and sawdust had been removed). Over a 90-min period of observation, both strains presented a time-dependent decrease of locomotion and leaning and an increase of grooming. C57 mice were characterized by more cage cover climbing than DBA mice during the first 15-min stay in the new cage and by a significant decrease of this behavior after 90 min. During the first 60 min in the new environment, the DBA mice were less active than C57 mice, and both strains presented a significant increase of immobility after 90 min of test. After 30 min in the test situation, C57 presented a larger increase of plasma corticosterone levels than DBA mice. The plasma corticosterone levels were back to control values after 60 min of test in mice of the C57 strain and after 90 min in the DBA strain. Finally, both C57 and DBA mice presented a significant increase of homovanillic acid concentrations in the nucleus accumbens, but not in the striatum at 30, 60 and 90 min of testing. These results are discussed in terms of the possible involvement of mesolimbic dopaminergic system in mouse behavioral responses to an unfamiliar environment and of possible habituation to the stressful properties of this experience.

Aging and food restriction: Effect on lipids of cerebral cortex

In experimental animals dietary restriction reduces the body weight increase due to aging, increases longevity and delays the onset of age-related physiological deterioration, including age-related changes in serum lipids. Little is known about the influence of food restriction on brain lipids, whose concentration and composition have been shown to change with age. We studied whether some biochemical and biophysical parameters of rat brain membranes, known to be modified with age, were affected by a diet low in calories, in which 50% of lipids and 35% of carbohydrates have been replaced by fibers. The diet was started at weaning and maintained throughout the animals entire life span. Animals fed the low calorie diet survived longer and gained less body weight than standard diet fed rats. Age-related increases in microviscosity, cholesterol/phospholipid and sphingomyelin/phosphatidylcholine ratios were reduced or restored to the levels of young animals in cortex membranes of 32 old rats fed the low calorie diet, while the age-related increase in mono- to polyunsaturated fatty acid ratios in phospholipids was further raised. In conclusion we have shown that a diet low in calories and high in fibers affects lipid composition in the rat brain, in a direction opposite to that normally believed to reduce age-related deterioration of brain functions.

Age-related ability of rats kept on a life-long hypocaloric diet in a spatial memory test. Longitudinal observations.

Cognitive behavior was assessed in a test specific for spatial memory, according to a longitudinal experimental model, in populations of 12-, 24- and 30-month-old rats which were fed ad lib either a standard (ST) or a hypocaloric (HY) diet, that had been shown to reduce age-related pathologies and to increase survival. Already at 12 months of age, some cognitive deficits were observed in ST but not in HY rats. When retested 12 and 18 months later, the animals performed better at the beginning of the test than when tested for the first time, indicating that some aspects of previous experience lead to a preservation of spatial memory. Deficits which had been previously observed in 2-year-old groups in a cross-sectional experimental model were not evident this time. Some of the differences between the two diet groups observed 12 months before disappeared. When testing was repeated for the third time at 30 months of age, ST fed rats presented very marked deficits in learning and in memory, which were not seen in the HY group. It thus appears that a dietary regimen in which part of the calorie-rich components, such as lipids and carbohydrates, are replaced with vegetable fibers, retards some of the age-related deteriorations of brain functions.