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Biomedical subjects

X A Alvarez

Publications and source records attributed to X A Alvarez.

At least 19 recordsLinked to original sources
PubMed2001

Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease.

In the brains of patients with Alzheimer's disease (AD) signs of neuronal degeneration are accompanied by markers of microglial activation, inflammation, and oxidant damage. The presence of nitrotyrosine in the cell bodies of neurons in AD suggests that peroxynitrite contributes to the pathogenesis of the disease. A drug with antioxidant and anti-inflammatory activity may prevent neuronal degeneration in AD. Celastrol, a plant-derived triterpene, has these effects. In low nanomolar concentrations celastrol was found to suppress the production by human monocytes and macrophages of the pro-inflammatory cytokines TNF-alpha and IL-1beta. Celastrol also decreased the induced expression of class II MHC molecules by microglia. In macrophage lineage cells and endothelial cells celastrol decreased induced but not constitutive NO production. Celastrol suppressed adjuvant arthritis in the rat, demonstrating in vivo anti-inflammatory activity. Low doses of celastrol administered to rats significantly improved their performance in memory, learning and psychomotor activity tests. The potent antioxidant and anti-inflammatory activities of celastrol, and its effects on cognitive functions, suggest that the drug may be useful to treat neurodegenerative diseases accompanied by inflammation, such as AD.

Alzheimer Disease↗
PubMed2000

Cerebrolysin reduces microglial activation in vivo and in vitro: a potential mechanism of neuroprotection.

Neurotrophins, such as NGF, BDNF and NT-3 play a regulatory role on the function of microglial cells in vivo and in vitro, and the identification of new compounds with neurotrophic properties is becoming a new strategy for the prevention and/or treatment of neurodegenerative disorders. In this study we describe the use of two different models to demonstrate the ability of Cerebrolysin to reduce microglial activation. The results of these in vitro and in vivo studies indicate that Cerebrolysin might exert a neuroimmunotrophic activity reducing the extent of inflammation and accelerated neuronal death under pathological conditions such as those observed in neurodegenerative diseases.

Amino Acids↗
PubMed2000

Oral Cerebrolysin enhances brain alpha activity and improves cognitive performance in elderly control subjects.

Cerebrolysin is a porcine brain derived peptide preparation with potential neurotrophic activity. The effects of a single oral dose of the Cerebrolysin solution (30 ml) on brain bioelectrical activity and on cognitive performance were investigated in healthy elderly people. A single oral dose of Cerebrolysin induced a progressive increase in relative alpha activity power from 1 to 6 hours after treatment in almost all the brain electrodes in elderly control subjects. As compared with baseline alpha power (45.8+/-9.5%), the increase in relative alpha activity in the left occipital electrode (O1) reached significant values at 1 hour (57.2+/-8.5%; p < 0.05), 3 hours (59.4+/-7.6%; p < 0.05) and 6 hours (63.4+/-9.8%; p < 0.05) after Cerebrolysin administration. Enhancement in relative alpha power was accompanied by a generalized decrease in slow delta activity that was maximum at 6 hours after Cerebrolysin intake. A significant improvement in memory performance, evaluated with items of the ADAS cog, was also found in elderly people taken a single dose of oral Cerebrolysin (6.9+/-1.0 errors at baseline versus 4.9+/-1.0 errors after treatment; p < 0.01). This memory improvement was more evident in recognition (2.8+/-0.6 errors vs. 1.5+/-0.7 errors; p < 0.05) than in recall tasks (4.1+/-0.5 errors versus 3.4+/-0.5 errors; ns). These data indicate that Cerebrolysin potentiates brain alpha activity, reduces slow EEG delta frequencies and improves memory performance in healthy elderly humans, suggesting that this compound activates cerebral mechanisms related to attention and memory processes. According to the present results, it seems that oral Cerebrolysin might be useful for the treatment of memory impairment and brain damage in eldely subjects with or without neurodegenerative disorders.

Administration, Oral↗
PubMed2000

Double-blind, randomized, placebo-controlled pilot study with anapsos in senile dementia: effects on cognition, brain bioelectrical activity and cerebral hemodynamics.

The aim of this study was to evaluate the effects of two doses of anapsos in comparison with placebo on cognitive performance, brain bioelectrical activity pattern and cerebral hemodynamic parameters in patients with mild to moderate senile dementia of vascular type and Alzheimer type. Forty-five patients (age 73.8 +/- 7.6 years; range 56-89 years) with mild to moderate senile dementia (Global Deterioration Scale: stages 3-5) of the vascular (VD; n = 22) or the Alzheimer type (AD; n = 23) were included in a double-blind randomized placebo-controlled clinical trial. After a 2-week period of drug washout, patients were treated with placebo (n = 15; age 72.7 +/- 7.5 years), 360 mg/day of anapsos (n = 15; age 75.5 +/- 7.2 years), or 720 mg/day of anapsos (n = 15; age 73 +/- 7.7 years) for 4 weeks (28 days). At baseline and after the 4-week period of double-blind treatment, cognitive performance, brain bioelectrical activity power and blood flow hemodynamics in the middle cerebral arteries were evaluated with ADAScog, brain mapping and transcranial Doppler ultrasonography, respectively. Patients receiving 360 mg/day of anapsos showed a significant improvement in cognitive performance after treatment (ADAScog scores: p < 0.05) that was not observed in patients treated with placebo or 720 mg/day of anapsos. As compared to placebo, anapsos (360 mg/day) induced a significant improvement in ADAScog scores in mild senile dementia patients (p < 0.01) and in the subset of patients with AD (p < 0.05). Anapsos (360 mg/day) also increased cerebral blood flow velocities in left and right middle cerebral arteries in the subgroup of AD patients, whereas with the dose of 720 mg/kg this increase was only observed in the left side. Patients treated with anapsos (360 mg/day) showed a decrease in relative delta power and an increase in relative theta and alpha brain bioelectrical activity frequencies, indicating an acceleration of the EEG pattern. The present results show that anapsos (360 mg/day) improves cognitive performance, cerebral blood perfusion and brain bioelectrical activity in patients with senile dementia. These effects of anapsos were more marked in demented patients with mild mental deterioration and/or with dementia of the Alzheimer type.

Adjuvants, Immunologic↗
PubMed1999

Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats.

Citicoline is an endogenous intermediate involved in the biosynthesis of brain phospholipids and acetylcholine which has been extensively used for the treatment of several neurodegenerative conditions. The effects of citicoline on neurodegeneration, apoptosis and learning were investigated in male Sprague Dawley rats subjected to implants of the beta-amyloid fragment 1-40 (A beta 4: 3 Mmol) into the right hippocampus and to permanent unilateral occlusion of the carotid artery. Citicoline (CDP; 0, 62.5, 125 and 250 mg/kg/day i.p.) was given during 2 days before and for 5 days after surgery, and the extension of the degeneration and the number of apoptotic figures (TUNEL technique) were evaluated in the dentate gyrus (DG) and the CA1 area of the hippocampus. Citicoline, at 125 and 250 mg/kg, reduced the number of apoptotic neurons in the hippocampus of rats with A beta 4/hypoperfusion-induced neurodegeneration (CDP0 = 105.3 +/- 32.8 apoptotic figures; CDP125 = 39.2 +/- 7.4** apoptotic figures; CDP250 = 34.5 +/- 14.4** apoptotic figures; **p < 0.01 vs. CDP0). CDP also reduced neuronal degeneration in the CA1 area in a dose-dependent manner (CDP0 = 450.5 +/- 130.1 microns; CDP62.5 = 280.6 +/- 76.3 microns; CDP125 = 86.6 +/- 37.3* microns; CDP250 = 121.7 +/- 85.3* microns; p < 0.05 vs. CDP0). Variability of results was very high in the DG, where a significant reduction in the extent of neurodegeneration was only observed in the group of rats receiving 62.5 mg/kg of citicoline. Finally, citicoline improved retention of a passive avoidance learning task, increasing the number of avoidances (Av) (CDP0 = 4.2 +/- 0.7 Av; CDP62.5 = 6.9 +/- 1.0 Av; CDP125 = 7.9 +/- 0.7** Av; CDP250 = 8.5 +/- 0.6** Av; **p < 0.01 vs. CDP0) in a dose-related manner. Based on these results, it was concluded that citicoline exerts antiapoptotic, neuroprotective and antiamnesic effects in conditions of neurodegeneration induced by A beta 4 plus hypoperfusion.

Amyloid beta-Peptides↗
PubMed1999

Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion.

Cytidine 5'-diphosphocholine (citicoline) is a an endogenous intermediate in the biosynthesis of structural membrane phospholipids and brain acetylcholine. Citicoline has been extensively used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, cerebrovascular pathology and Alzheimer's disease. In this study we have investigated the efficacy and safety of the treatment with citicoline versus placebo in patients with Alzheimer disease. Thirty patients (age = 73.0 +/- 8.5 years; range = 57-87 years) with mild to moderate senile dementia (GDS: stages 3-6) of the Alzheimer type were included in a double-blind, randomized and placebo-controlled clinical trial. After a 2-week period of drug washout, patients were treated with i) placebo (n = 17; age = 73 +/- 5 years) or ii) 1,000 mg/day of citicoline (n = 13; age = 76 +/- 9 years) for 12 weeks (84 days). Examinations were done at baseline (T0) and after the 12 weeks of treatment (T12). As compared to placebo, citicoline improved cognitive performance in Alzheimer's disease patients with APOE E4 (ADAS: difference between groups = -3.2 +/- 1.8 scores, p < 0.05; ADAS-cog: difference between groups = -2.3 +/- 1.5, ns); and this improvement on cognition was more pronounced (ADAS, p < 0.01; ADAS-cog: difference between groups = -2.8 +/- 1.3, p < 0.06) in patients with mild dementia (GDS < 5). Citicoline also increased cerebral blood flow velocities in comparison with placebo (p < 0.05) when transcranial Doppler recordings from both hemispheres were considered together, as well as diastolic velocity in the left middle cerebral artery (p < 0.05). Patients treated with citicoline showed an increase in the percentage of brain bioelectrical activity of alpha (occipital electrodes) and theta type (left side electrodes), accompanied by a decrease in relative delta activity particularly marked in the left temporal lobe. Significant differences with respect to placebo (p < 0.05) were observed for theta activity in several fronto-parieto-temporal electrodes of the left hemisphere. Treatment with citicoline tended to reduce serum IL-1 beta levels, mainly after 4 weeks of administration, with no modified blood histamine content. In addition, neither adverse side effects nor alterations in biological and hematological parameters were induced by citicoline. The present data indicate that citicoline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion and the brain bioelectrical activity pattern in AD patients. According to our results, it seems that citicoline might be a useful treatment in Alzheimer's disease, and that the efficacy of this compound is greater in patients with mild mental deterioration and/or bearing the epsilon 4 allele of the APOE.

Aged↗
PubMed1997

A general method for DNA polymorphism identification in genetic assessment and molecular diagnosis.

A general methodology for the analysis of human diseases at the nucleic acid level has been described. This method consists of a semiautomated, nontoxic analytic procedure, staining DNA bands with silver nitrate instead of ethidium bromide after DNA amplification by PCR. This technique provides a sensitive assay with enhanced accuracy and offers the possibility of carrying out the molecular analysis of several polymorphisms in a single day simplifying molecular genetics with diagnostic purposes.

DNA↗
PubMed1997

Effects of anapsos on the activity of the enzyme Cu-Zn-superoxide dismutase in an animal model of neuronal degeneration.

The enzyme Cu-Zn-SOD is a metalloenzyme that catalyzes the dismutation of the superoxide radical into hydrogen peroxide and molecular oxygen, being a defense system against free radical formation. Free radical reactions are implicated in a variety of physiological and pathological processes as aging, apoptosis and neurodegenerative diseases, and abnormalities associated with SOD have been recently documented in several neurodegenerative processes. In this study, we have evaluated the effect of anapsos on Cu-Zn-SOD activity in rats with injections of beta-amyloid protein or water bilaterally into the hippocampus. These injections caused severe cell depletion in the gyrus dentatus. Anapsos is a biological extract obtained from the fern Polypodium leucotomos with immunomodulatory and anti-neoplastic effects tested in animals and humans. Cu-Zn-SOD activity was measured in the hypothalamus, hippocampus, cerebral cortex, liver and spleen of rats treated i.p. with three doses of anapsos for 7 days (4, 20 and 100 mg/kg/day). Control animals were treated with saline solution under the same conditions. Anapsos significantly modified enzyme activity in all the areas tested. Lower doses of anapsos produced decreased SOD activity in the hypothalamus, hippocampus, liver and spleen, while in the cerebral cortex, a significant dose-dependent increase in SOD activity was observed. These results indicate that anapos was able to modify Cu-Zn-SOD activity in this animal model of neuronal degeneration, which may indicate the participation of anapsos in mechanisms of tissue repair after brain damage.

Amyloid beta-Peptides↗
PubMed1997

Citicoline improves memory performance in elderly subjects.

Citicoline is a choline donor involved in the biosynthesis of brain phospholipids and acetylcholine extensively used in the treatment of neurodegenerative diseases. In this study we investigated the effects of the oral administration of citicoline alone (C1000:1000 mg/day; C500:500 mg/day) or in combination with nimodipine (C +NI:300 + 90 mg/day) during 4 weeks on memory performance in elderly subjects with memory deficits and without dementia (N = 24; age = 66.12 +/- 10.78 years; MMS score = 31.69 +/- 2.76). Results indicated that citicoline in comparison with placebo improves memory in free recall tasks, but not in recognition tests. A significant improvement in word recall (5.17 +/- 1.1 vs. 3.95 +/- 1.2 omissions; p < 0.005), immediate object recall (6.5 +/- 1.6 vs. 5.5 +/- 1.2 omission; p < 0.05) and delayed object recall (8.5 +/- 2.1 vs. 6.7 +/- 2.4 omissions; p < 0.005) was observed after citicoline treatment. Similar results were found in the three subgroups of treatment (8 subjects per group), suggesting that citicoline possesses memory-enhancing activity at doses of 300-1000 mg/day. A decrease in systolic blood pressure and minor changes in lymphocyte cell counting were also observed in old subjects after receiving citicoline. These effects are consistent with the vasoregulatory and neuroimmune actions of citicoline and suggest that this compound may improve memory by acting on mechanisms of brain neurotropism and cerebrovascular regulation. According to the present results, showing that citicoline improves memory performance in elderly subjects, we concluded that this molecule is suitable for the treatment of memory deficits in old people.

Aged↗
PubMed1997

Anapsos reverses interleukin-1 beta overexpression and behavioral deficits in nbM-lesioned rats.

Rats with neurotoxic lesions, induced by single or double bilateral injections of ibotenic acid into different parts of the nucleus basalis of Meynert (nbM), showed increased psychomotor activity (PMA) and impaired learning in a passive avoidance task. Behavioral deficits were similar in all the groups of lesioned animals, suggesting that the lesion site was not relevant for the ibotenic effects under testing procedures used here. In another experiment, nbM-lesioned rats received acute or daily (5 days) i.p. injections of vehicle or anapsos (100 mg/kg) from the 7th day after surgery. Data indicated that nbM lesions induced an increased production of interleukin-1 beta (IL-1 beta), motor hyperactivity and learning impairment, and that anapsos, a vegetal extract with immunomodulatory activity, reversed brain IL-1 beta overexpression and behavioral alterations in lesioned rats. These results confirm the involvement of IL-1 beta in neurodegeneration associated with cholinergic deficits and the potential utility of compounds with neuroimmunotrophic activity as a new therapeutic strategy in neurodegenerative disorders.

Adjuvants, Immunologic↗
PubMed1997

Intrahippocampal injections of the beta-amyloid 1-28 fragment induces behavioral deficits in rats.

beta-amyloid (beta A) deposition is a key event in the etiopathogenesis of Alzheimer's disease (AD), contributing to neuronal degeneration and cognitive impairment in AD patients. Both neurotrophic and neurotoxic actions of beta A have been demonstrated in experimental conditions. In order to further characterize the effects of brain beta A deposits on behavioral processes, we evaluated psychomotor activity (PMA), psychomotor coordination (PMC) and learning in a passive avoidance task (PAL) in rats with unilateral or bilateral 2 microliters injections of beta-amyloid (1-28) protein (beta A; 1.5 nmol/microliter) or vehicle (water; W) into the hippocampus, 1 and 4 weeks after neurosurgery. The extent of neuronal loss in the lateral blade of the gyrus dentatus (LBGD) and the area percentage occupied by APP immunoreactivity in neurons of the CA3c subfield of the hippocampus were also measured in animals with unilateral beta A implants. PMA levels were similar in water- and beta A-injected animals 1 and 4 weeks after recovery. As compared to water-injected rats, beta A animals showed reduced PMC values 1 week, but not 4 weeks, after injections. beta A also impaired learning acquisition in a passive avoidance task, reducing the number of avoidances and mean latency per trial at both 1 and 4 weeks postsurgery in rats with unilateral or bilateral beta A implants. The extent of neuronal loss in the LBGD) was not different in rats receiving water or beta A injections. Hippocampal APP expression tended to increase in beta A-implanted rats and showed a negative correlation with cognitive performance at the 4-week period. According to these results it seems that beta A implants into the hippocampus reduce psychomotor coordination performance in a transient manner, with no effect on psychomotor activity, and induce durable learning impairment in rats, and that changes in cognitive performance correlate with histochemical parameters such as APP expression. In conclusion, the present results contribute to a better understanding of beta A-induced behavioral alterations and to the identification of potential molecular mechanisms involved in cognitive dysfunctions in this animal model of neurodegeneration.

Alzheimer Disease↗
PubMed1996

Therapeutic effects of CDP-choline in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors.

CDP-choline was given to patients with Alzheimer's disease (AD) at a daily dose of 1000 mg/day p.o. for one month. This compound slightly improved mental performance, tended to reduce theta activity in fronto-temporal regions, increasing alpha power in occipital areas, and enhanced cerebrovascular perfusion by increasing blood flow velocity and reducing pulsatility and resistance indexes. In addition, CDP-choline diminished histamine and interleukin-1 levels in blood and serum, respectively, and increased plasma TNF.

Aged↗
PubMed1996

Effects of S-9977-2 on histamine levels in rats.

S-9977-2 is a new molecule with promnesic and antiamnesic properties. In this study, we investigated the effects of i.p. administration of S-9977-2 on histamine (HA) levels in several regions of the rat brain, and also in peripheral areas, using high performance liquid chromatography (HPLC) with fluorometric detection. S-9977-2 (0.025 mg/kg) induced an increase in the content of HA in the anterior hypothalamic region, with a significant effect 30 min after injection (1.77 +/- 0.36 nmol/g vs. 2.43 +/- 0.40 nmol/g; p < 0.01). It did not significantly modify HA levels in the posterior hypothalamic region, hippocampus, fronto-parietal cortex, blood, spleen, or adrenal glands. A clear tendency to increase HA content was observed in the hippocampus (0.16 +/- 0.03 nmol/g vs. 0.39 +/- 0.31 nmol/g, ns) and fronto-parietal cortex (0.55 +/- 0.45 nmol/g vs. 0.70 +/- 0.28 nmol/g; ns). S-9977-2 at doses of 0.005 and 0.125 mg/kg i.p. did not produce any significant change in HA levels in any of the samples tested 30 min after administration. The present results demonstrate that S-9977-2 increases HA levels in the anterior hypothalamus, which is the brain region with the highest content in histaminergic fibers. This fact suggests that the neuronal HA system might be involved directly or indirectly in the pharmacological actions of S-9977-2.

Adrenal Glands↗
PubMed1995

Effects of histamine and alpha-fluoromethylhistidine on brain tumor necrosis factor levels in rats.

Besides the role of histamine (HA) as a neurotransmitter, a new concept has emerged presenting HA as an immunomodulator. Several studies have demonstrated interactions among HA, interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF), suggesting a possible bidirectional communication among them. In this study we have investigated the effects of i.p. administrations of HA diphosphate (6 mumol/kg) and alpha-fluoromethylhistidine (FMH; 100 mg/kg) on TNF-alpha levels in the hippocampus, hypothalamus, and posterior hypothalamic region of the rat brain. The concentrations of TNF-alpha at 0 (Control, C) and 30 min after i.p. administration of HA were 0.26 +/- 0.02 pg/mg and 0.32 +/- 0.02 pg/mg in the hippocampus, 0.46 +/- 0.04 pg/mg and 0.09 +/- 0.006 pg/mg (p < 0.01) in the hypothalamus, and 0.47 +/- 0.05 pg/mg and 0.26 +/- 0.05 pg/mg in the posterior hypothalamic region. Three hours after FMH administration, an increase in the hippocampal levels of TNF-alpha was observed (0.43 +/- 0.04 pg/mg; p < 0.01), while in the hypothalamus (0.11 +/- 0.02 pg/mg; p < 0.01) and in the posterior hypothalamic region (0.21 +/- 0.04 pg/mg; p < 0.05) a decrease in TNF-alpha levels was detected. These results suggest that changes in the histaminergic system influence TNF-alpha production in the brain in an area-specific fashion.

Animals↗