Biomedical subjects
R Cacabelos
Publications and source records attributed to R Cacabelos.
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.
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.
Allelic variants of the thiopurine methyltransferase (TPMT) gene in the Colombian population.
Thiopurine methyltransferase (TPMT) catalyzes the inactivation of thiopurine drugs (mercaptopurine, thioguanine and azathioprine) used to treat acute lymphoblastic leukemia, autoimmune diseases and recipients of transplanted organs. No endogenous substrates for this enzyme are known. The TPMT polymorphism is a major determinant of individual differences in the toxicity or therapeutic efficacy of these drugs. The molecular basis of this polymorphism has been established in Caucasians, Africans, African-Americans and Asians, but not yet in the heterogeneous Latin American groups, including the Colombian population. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G), were determined in 140 Colombian volunteers of Mestizo origin, using allele-specific PCR and PCR-RFLP assays. The *3A allele was found in 10 samples and the *2 allele in one, all heterozygotes; neither homozygous mutant genotypes nor the *3B and *3C alleles were detected. In agreement with these results, 92.1% and 7.9% of the Colombian population correspond to the phenotypes high and intermediate methylators, respectively. These results show that the frequency of mutations and the allelic distribution of the TPMT gene in the Colombian population are similar to the genetic profile found among US and European Caucasian populations, where the *3A allele is prevalent and the *2 allele is currently present.
Genomics and phenotypic profiles in dementia: implications for pharmacological treatment.
Constitutive genomics are probably determinant for the onset of dementia in conjunction with cerebrovascular and environmental factors. Furthermore, pharmacogenomic studies predict that the therapeutic response in Alzheimer's disease (AD) is genotype-specific, and that the expression of genes involved in the regulation of drug metabolism can influence efficacy and safety issues in pharmacotherapy. AD and dementia with a vascular component (DVC = VD + MXD) are the most prevalent forms of dementia. These clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folic acid and vitamin B(12) levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: (a) anthropometric values, (b) cardiovascular function, (c) blood pressure, (d) lipid metabolism, (e) uric acid levels, (f) peripheral calcium levels, (g) liver function (GOT, GPT, GGT), (h) alkaline phosphatase, (i) lactate dehydrogenase, (j) red and white blood cells, (k) regional brain atrophy (left temporal region, inter-hippocampal distance) and (l) brain blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30 to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0 to 5%. The relative polymorphic variation in genetic clusters integrated by 2, 3 or 4 genes associated with AD ranges from 1 to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are essential for the expression of dementia symptoms that might be accelerated or induced by environmental and/or cerebrovascular factors.
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.
GRF-induced GH response in attention-deficit hyperactivity disorder.
Attention-deficit hyperactivity disorder (ADHD) is a type of disruptive behavior of unknown etiology with a prevalence of 2.5-5% in school-age children. The useful evaluation of the GRF-induced GH response as a marker in some mental disorders led us to study the response of GH to the exogenous administration of GRF (1-29) NH2 (150 micrograms, i.v.) in ADHD children (N = 12, age = 7.78 +/- 1.66 years) and healthy children (N = 6; age = 8.73 +/- 2.24 years) in order to evaluate the functioning of the somatotropinergic system (GRF-SS-GH-SM axis) and using this neuroendocrine test as a potential diagnostic marker and/or a therapeutic predictor in ADHD. While controls (CS) showed a maximum GH response to GRF 15 min after injection (37.15 +/- 29.56 ng/ml; basal GH = 5.49 +/- 4.71 ng/ml), ADHD children (basal GH = 2.28 +/- 1.66 ng/ml) exhibited a lower response with a plateau from 15 (21.32 +/- 10.00 ng/ml) to 60 min (26.48 +/- 23.72 ng/ml). Serum GH levels at 90 (17.23 +/- 14.45 vs. 5.99 +/- 2.82 ng/ml, p less than 0.05) and 120 min (11.89 +/- 8.63 vs. 4.12 +/- 1.66 ng/ml, p less than 0.05) were significantly higher in ADHD than in CS. According to the GRF-induced GH response elicited in ADHD, two different populations of patients can be distinguished; one group with high response of GH (AUC = 3372.21 +/- 1127.61 ng.min/ml) and another group with a hyporeactive GH (AUC = 1567.46 +/- 726.0 ng.min/ml, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Serum tumor necrosis factor (TNF) in Alzheimer's disease and multi-infarct dementia.
Changes in neuroimmune parameters and cytokine production have been reported in patients with Alzheimer's disease, including increased levels of interleukin-1 (IL-1) and histamine in brain tissue, cerebrospinal fluid and serum. Specific neuroimmune reactions may be responsible in part for astrogliosis and neuronal death in particular circumstances. Since IL-1 and tumor necrosis factor (TNF) tend to act synergistically in physiological conditions and in some pathological processes, we have studied the concentration of TNF-alpha in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and in age-matched control subjects (CS) in order to evaluate possible changes in the levels of this cytokine with potential influence on the pathogenesis of AD. Serum TNF-alpha levels were significantly lower in AD (2.5 +/- 1.25 pg/ml, p < 0.01) and MID (1.64 +/- 1.17 pg/ml, p < 0.001) than in CS (10.66 +/- 8.92 pg/ml). A negative correlation between serum TNF-alpha levels and age in AD was found (r = -0.645, p < 0.01); however, no significant correlations were detected between serum TNF-alpha levels and mental performance, cerebrovascular risk, heart rate and blood pressure in either AD or MID. In conclusion, there is a marked reduction in the concentration of serum TNF-alpha in both AD and MID which seems to be poorly related to cognitive dysfunction and/or neurovascular damage, probably reflecting an endogenous immune dysregulation and/or an inhibitory reactive process in demented patients.
An experimental model to study the cytotoxic effects induced by beta-amyloid, histamine, LPS and serum from Alzheimer patients on cultured rat endothelial cells.
Lactate dehydrogenase (LDH) enzyme activity was measured in the supernatant of rat aortic endothelial cell cultures to evaluate the cytotoxic effects of two proinflammatory mediators such as LPS and histamine, as well as beta-amyloid protein (fragment 1-28) on endothelial cells. In the same culture we also studied the influence of different sera from patients with Alzheimer's disease (AD) or healthy elderly subjects. The results indicate that very low concentrations (1 microgram/ml) of beta-amyloid or histamine (1 microM) were able to produce cell damage after an incubation time of 4 h. Treatment with LPS induced cell damage at the highest concentration (2.5 micrograms/ml) after 24 h of incubation. When endothelial cells were treated with serum from AD and non-AD individuals, an inhibition of endothelial cell proliferation was observed only with activated AD serum. These results indicate that rat endothelial cell cultures represent an important model to study inflammatory mediators and to evaluate the therapeutic effect of antiinflammatory molecules in AD and other neurodegenerative disorders.