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Biomedical subjects

X A Alvarez

Publications and source records attributed to X A Alvarez.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1994

Effects of neurotoxic lesions in the posterior hypothalamic region on psychomotor activity and learning.

Histamine (HA) acts as a neurotransmitter and/or neuromodulator in mammalian brain. Central HA has been found to be involved in the regulation of behavioral, cognitive, neurovegetative, neuroendocrine and neuroimmune functions. In this study we have evaluated psychomotor activity (PMA) and passive avoidance behavior (PAB) in rats with bilateral neurotoxic lesions in the posterior hypothalamic region (PHR) (L), where histaminergic neurons are located, and in sham-operated rats (S), two weeks after neurosurgery. In an open-field paradigm, lesioned rats showed higher PMA scores than sham-operated animals. However, L rats exhibited a significant decrease in PMA on consecutive days (motor habituation) similar to that found in S rats. In a maze paradigm, in which the animals had to learn to stay on a neutral platform in order to avoid a 1.5 mA electric footshock during 10 trails, no significant differences were observed between L and S rats on the task performance. According to the present results, it seems that bilateral neurotoxic lesions in the PHR induced hyperactivity with no apparent effects on PAB, suggesting that neuronal HA might be involved, directly and/or by influencing arousal/alertness-mediated mechanisms, in the regulation of PMA processes.

Analysis of Variance↗
PubMed1994

Effects of neurotoxic lesions in histaminergic neurons on brain tumor necrosis factor levels.

Histamine (HA) is a biogenic amine involved in the regulation of neurovegetative, cognitive, neuroendocrine and neuroimmune functions in the central nervous system (CNS). A bidirectional interaction between the CNS and the neuroimmune system has been demonstrated in recent years. However, data concerning brain HA-cytokine interactions are scarce. In this study we have evaluated tumor necrosis factor-alpha (TNF-alpha) levels in the posterior hypothalamic region (PHR) and hippocampus (HP) of rats with: (a) bilateral ibotenic acid neurotoxic lesions in histaminergic neurons located in the PHR (I); (b) saline injections in the PHR (S); and (c) sham operation (C), two weeks after neurosurgery. The bilateral disruption of PHR HA neurons with ibotenic acid decreased TNF-alpha levels in the PHR with respect to sham-operated (C), but not saline-injected (S), rats. In contrast, hippocampal TNF-alpha concentrations were higher in lesioned rats (I) than in C and S animals. Our results indicate that the neurotoxic destruction of HA neurons decreases TNF-alpha synthesis in the hypothalamus while enhancing TNF-alpha production in the hippocampus, suggesting that neuronal HA might be involved in the regulation of the brain TNF-alpha system.

Animals↗
PubMed1994

Brain interleukin-1 beta in Alzheimer's disease and vascular dementia.

Recent investigations indicate that a neuroimmune reaction, associated with inflammatory mechanisms, can contribute in Alzheimer's disease (AD) to cell damage and neurodegeneration. Activation of microglial cells, expression of immunohistochemical markers of brain immune function, the presence of complement proteins in brain tissue and changes in cytokine production have been reported in AD. We have studied the concentration of interleukin-1 beta (IL-1 beta) in different regions of the central nervous system (CNS) in post-mortem samples from patients with AD or vascular dementia (VD) and in age-matched control subjects (CS). IL-1 beta levels were significantly higher in AD than in VD or CS in the frontal cortex, parietal cortex, temporal cortex, hypothalamus, thalamus and hippocampus. The highest increases in IL-1 beta levels were observed in the frontal cortex (CS = 0.75 +/- 0.045; AD = 2.47 +/- 0.12, p < 0.001; VD = 1.52 +/- 0.078 pg/mg, p < 0.001) and hippocampus (CS = 0.71 +/- 0.042; AD = 2.63 +/- 0.19, p < 0.001; VD = 1.21 +/- 0.23 pg/mg, p < 0.01). No significant changes were detected in the occipital cortex and cerebellum in either AD or VD. These results clearly demonstrate that demented patients show a generalized increment of IL-1 beta production in the CNS, with maximum response in those brain regions where AD neuropathology is most prominent. This overall increase in cytokine production might represent an early event in the activation of a neuroimmune cascade leading to cell death and neurodegeneration in brain regions where a primary cause (e.g., genetic, toxic, vascular) facilitates the induction of resting microglia for firing brain immune function.

Aged↗
PubMed1994

CDP-choline-induced blood histamine changes in Alzheimer's disease.

Histamine (HA) is a known neurotransmitter with a wide spectrum of biological actions at the central and peripheral levels. Recently, it has been found that HA is involved in the regulation of immune cell function, acting as an immunomodulator. A hyperactivation in the histaminergic system has been demonstrated in Alzheimer's disease (AD), including increased levels of HA in brain, serum, and cerebrospinal fluid of AD patients. In addition, changes in phospholipid metabolism and neuroimmune function have been reported in AD. CDP-choline (cytidine-5-diphosphate-choline) participates in the phospholipid metabolism pathway incorporating free choline into phosphatidyl-choline and choline plasmalogens in several tissues, including the central nervous system. In this study we have measured the concentration of HA in blood from patients with early-onset AD (EOAD) and late-onset AD (LOAD) under treatment with CDP-choline (1000 mg p.o. x30 days). HA was measured by high performance liquid chromatography (HPLC) with fluorometric detection. CDP-choline reduced the basal levels of blood HA in both EOAD and LOAD by 2-fold. The reduction in blood HA content was observed 2 h after CDP-choline administration and gradually progressed for 30 days of treatment. These results confirm the potential immunogenic effects of CDP-choline and also that an excess of HA might influence some etiopathogenic events in AD.

Administration, Oral↗
PubMed1993

Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia.

The cholinergic dysfunction present in Alzheimer's disease (AD) might be due to a specific vulnerability of cholinergic neurons linked to neurotrophic imbalance, neuroimmune impairment, and/or direct effects of beta-amyloid deposition and NFT formation in ACh neurons. The presence of abnormal epitopes exposed on neuronal membranes may contribute to the activation of resting microglia initiating a neuroimmune cascade leading to cell destruction. According to this hypothesis, a multifactorial treatment in AD should produce: 1) inhibition of beta-amyloid and NFT formation; 2) restoration of neuronal membrane integrity; and 3) control of neuroimmune auto-aggression. Since interleukin-1 (IL-1) is an APP gene promoter showing a progressive increase in body fluids in parallel with mental deterioration in AD patients, we have studied the effects of CDP-choline on cognition, several biological parameters, and IL-1 beta production in AD and multi-infarct dementia (MID) in order to elucidate whether this compound alone or in combination with other drugs is able to restore immune function and improve mental performance in senile dementia.

Aged↗
PubMed1992

Serum histamine in Alzheimer's disease and multi-infarct dementia.

Recent data indicate that a neuroimmune reaction might be responsible in part for neuronal death and cognitive deterioration in senile dementia. The potential involvement of brain histamine (HA) and interleukin-1 (IL-1) in this process has been previously documented. We have studied the concentration of serum HA in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and in age-matched control subjects. Serum HA levels were significantly higher in AD (10.935 +/- 5.692 nM) and MID (8.521 +/- 3.44 nM) than in controls (5.533 +/- 2.567 nM) and correlated with mental performance as evaluated with the Mini-Mental State Examination (MMSE) (r = +0.493, p < 0.009). No correlation was found with cardiovascular parameters, cerebrovascular risk factors or age. Hyperactivation of the histaminergic system in AD at central and peripheral levels might reflect a neuroimmune reaction to brain tissue damage, a neurotrophic response, and/or a reactive process to regulate the IL-1 induced amyloid precursor protein (APP) overproduction.

Adult↗
PubMed1991

Histidine decarboxylase inhibition induced by alpha-fluoromethylhistidine provokes learning-related hypokinetic activity.

The influence of brain histamine (HA) on learning and memory is not well understood, although some reports indicate that HA improves memory consolidation. We have studied the effects of alpha-fluoromethylhistidine (FMH) (100 mg/Kg, i.p.), which reduced by 60-80% the concentration of hypothalamic HA, on rat locomotor activity (LA) and learning in several experimental conditions in a computerized system. FMH reduced LA in an open field paradigm (OFP) 3 h after injection and tended to inhibit motor habituation after a 3-day trial. In a maze paradigm (MP), where the animals had to learn to avoid a foot-shock (1 mA), FMH reduced LA, rearing (2F), and jumping activity (JA). The peripheral administration of HA to control-trained rats reduced a learning index (N/Sts ratio) by 50%. According to these results, FMH diminished LA, 2F, and JA with no effect on habituation in MP. These observations might indicate that a moderate reduction in the levels of brain HA might enhance attention in solving visuo-spatial tasks under stressful stimuli.

Animals↗
PubMed1991

Interleukin-1 in Alzheimer's disease and multi-infarct dementia: neuropsychological correlations.

It has been reported that patients with Alzheimer's disease (AD) exhibit an overproduction of interleukin-1 (IL-1) in the cerebrospinal fluid and brain tissue. Since IL-1 appears to promote the expression of the beta-amyloid precursor protein (APP) gene, we have investigated the concentrations of serum IL-1 alpha and IL-1 beta and AD and multi-infarct dementia (MID) in order to evaluate whether IL-1 acts as a peripheral activating factor on cerebrovascular endothelial cells stimulating APP production. Serum IL-1 alpha levels did not differ significantly between healthy elderly subjects (110.7 +/- 23.3 pg/ml), early-onset AD (EOAD; 112.5 +/- 23.3 pg/ml), late-onset AD (LOAD; 89.2 +/- 17.6 pg/ml) or MID (116.8 +/- 50.4 pg/ml) patients. Serum IL-1 beta levels were also similar in controls (223.7 +/- 55.7 pg/ml), EOAD (223.1 +/- 79.5 pg/ml), LOAD (212.5 +/- 58.9 pg/ml) and MID (199.4 +/- 29.0 pg/ml). In LOAD a negative correlation between mental performance (MMS score), IL-1 alpha (r = -0.7728; p less than 0.0715) and IL-1 beta (r = -0.9214; p less than 0.0011) was observed. These results indicate that serum IL-1 levels are not altered in AD and MID; therefore, it is unlikely that blood-borne IL-1 influences APP production in the central nervous system (CNS). In conclusion, the neuroimmune dysfunction present in AD seems to be mainly concentrated in the CNS, with only minor immune alterations at the peripheral level.

Aged↗
PubMed1991

Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer's disease and neurological disorders.

Recent studies indicate that patients with Alzheimer's disease (AD) exhibit an immune dysfunction at the central and peripheral levels. We have studied the concentration of IL-1 beta in the cerebrospinal fluid (CSF) of patients with AD, multi-infarct dementia (MID), normal pressure hydrocephalus (NPH), and multiple sclerosis (MS). CSF IL-1 beta levels were significantly higher in AD (131 +/- 17.33 pg/ml) than in MID (79.71 +/- 24.37 pg/ml, p less than 0.01), NPH (84.75 +/- 23.17 pg/ml, p less than 0.01), and MS (79.4 +/- 10.23 pg/ml, p less than 0.01). In patients with neurological disorders CSF IL-1 beta levels showed a progressive increase with age (r = +0.49, p less than 0.015). The concentration of IL-1 beta in CSF of demented patients correlated with mental deterioration (r = -0.476). According to these results we postulate that high levels of central IL-1 beta in AD might reflect a reactive neuroimmune response to: (a) abnormal epitopes exposed by lesioned neurons, (b) reactive microglia activated by exogenous and/or endogenous factors and (c) endogenous neurotrophic activation.

Aged↗
PubMed1990

Effects of GRF (1-29) NH2 on short-term memory: neuroendocrine and neuropsychological assessment in healthy young subjects.

Recent studies seem to indicate that the somatotropinergic system (STS) (GRF-SS-GH-SM axis) may be involved in the neuromodulation of higher activities of the central nervous system (CNS). In an attempt to demonstrate the influence of the STS on memory functions in humans, we have investigated the effects of acute administration of exogenous GRF vs. placebo on short-term memory (STM) in healthy young subjects. We gave GRF(1-29)NH2 (150 micrograms; i.v.) to a group of subjects (EG) (N = 17) and placebo (0.9% saline, 1 ml; i.v.) to a different group of subjects (CG) (N = 6). Prior to testing we presented a list of 20 neutral words (A1), and 2 hours after injection the same list (A2) and another list (B) of similar characteristics were presented in order to evaluate cognitive performance (CP). Basal CP (A1 list) was similar in EG and CG. Differences between EG and CG were found for both A2 (EG = 14.76 +/- 1.55 words vs. CG = 11.83 +/- 1.34 words, p less than 0.01) and B lists (EG = 12.17 +/- 1.68 words, p less than 0.005). According to the basal serum GH levels, EG subjects were divided into 2 subgroups: EG1 (N = 6), with high basal GH levels (11.57 +/- 4.47 ng/ml) and EG2 (N = 11), with low basal GH levels (1.55 +/- 1.71 ng/ml), similar to CG (1.3 +/- 1.53 ng/ml). GRF-induced GH response showed maxima 15 (28.15 +/- 11.71 ng/ml) and 30 min (28.09 +/- 17.07 ng/ml) after injection in EG1 and at 45 min (15.52 +/- 14.45 ng/ml) in EG2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease.

In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1 beta), and plasma tumor necrosis factor-alpha (TNF-alpha) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 age-matched control subjects (C). AD patients showed higher concentrations of histamine (AD = 452.9 +/- 237.9 pmol/mL; C = 275.3 +/- 151.5 pmol/mL; p < 0.05) and IL-1 beta (AD = 211.2 +/- 31.1 pg/mL; C = 183.4 +/- 24.4 pg/mL; p < 0.01), and lower values of TNF-alpha (AD = 3.59 +/- 2.02 pg/mL; C = 9.47 +/- 2.64 pg/mL; p < 0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-alpha were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1 beta values compared with age-matched controls. Age negatively correlated with histamine (r = -0.57; p < 0.05) and positively with IL-1 beta levels (r = 0.48; p < 0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-alpha scores and age was only found in AD patients (r = 0.46; p < 0.05). Furthermore, histamine and TNF-alpha values correlated negatively in AD (r = -0.50, p < 0.05). In addition, cognitive impairment increased in patients with lower TNF-alpha and higher histamine and IL-1 beta levels, as indicated by the correlations between mental performance scores and histamine (r = -0.37, ns), IL-1 beta (r = -0.33, ns) and TNF-alpha levels (r = 0.42, p < 0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r = -0.63, p < 0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.

Age of Onset↗
PubMedDate not supplied

Influence of growth hormone (GH) and GH-releasing factor on locomotor activity in rats.

Acute recombinant human growth hormone (r-hGH) administration (1-250 micrograms/kg; IP) decreased locomotor activity (LA) in a dose-dependent manner, F(5, 43) = 3.55, p < 0.009, with maximum effect at a dose of 10 micrograms/kg [control = 1655 +/- 659 inputs/outputs (I/O); r-hGH = 909 +/- 436 I/O; p < 0.05]. The daily treatment with r-hGH (10 micrograms/kg/day; 5 days; IP) reduced LA counts during the first trial, with no apparent changes in motor behavior after habituation. In contrast, growth hormone-releasing factor (GRF; 10 micrograms/rat/day; 5 days; IP) enhanced LA (control = 1045 +/- 566 I/O; GRF = 2284 +/- 894 I/O; p < 0.01) during the 5-day treatment period, inhibiting habituation. Moreover, the individual differences in LA persisted during the treatment period in response to GRF or r-hGH, but not in control rats. These results seem to indicate that the effects of GRF on LA are not mediated by the release of peripheral GH, and suggest that GRF might influence psychomotor behavior by a central mechanism.

Animals↗
PubMedDate not supplied

Antagonistic effects of growth hormone-releasing factor (GRF) and somatostatin on locomotor activity: GRF-induced hyperkinetic syndrome.

In order to investigate the potential antagonistic actions of the two main neuroregulators of the somatotropinergic system (GRF-SS-GH-SM axis), growth hormone-releasing factor (GRF) and somatostatin (SS) at the central level, the effects of GRF and SS on locomotor activity (LA) were studied in a computerized system. Male Wistar rats (N = 6-9 per group) received i.p. or i.c.v. GRF(1-44)NH2 or SS(1-14) in doses ranging from 0.1-30 micrograms, and LA was automatically recorded in the OUCEM-86 system (Osaka University Computerized Electronic Maze) for 30-min periods. The peripheral administration of SS (1 microgram, i.p.) did not alter LA, while GRF (1 microgram, i.p.) increased LA from 20.35 +/- 4.18 to 36.25 +/- 6.98 IO/min (p less than 0.005). After central injection, SS (1 microgram; i.c.v.) decreased LA from 31.16 +/- 6.90 to 20.88 +/- 2.82 IO/min (p less than 0.005) and GRF (1 microgram, i.c.v.) increased LA to 47.60 +/- 5.35 IO/min (p less than 0.005). SS- and GRF-induced LA changes were time- and dose-dependent (SS: ED50 = 1.83 nmol, Emax = 6.10 nmol; GRF: ED50 = 99.1 pmol, Emax = 1.98 nmol). The maximum effect of GRF appeared during the first 5 min, showing activity 10-15 sec post-injection, while the lowest activity induced by SS was registered 15-30 min after injection, although a significant reduction in LA was detected 5-10 sec after i.c.v. administration. With doses higher than 10 micrograms (i.c.v.) SS provoked "barrel rotation", tremors and stereotyped behaviors. The GRF-induced hyperkinetic syndrome showed a linear pattern with doses up to 10 micrograms, and a plateau with 10-15 micrograms. Doses higher than 20 micrograms induced convulsion, uncontrolled movements and a high death rate during the following 12-24 h. In conclusion, according to the present results, GRF and SS exert antagonistic effects on LA in a time- and dose-dependent manner, the former stimulating LA, and the latter inhibiting it.

Animals↗