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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.

HA is a biogenic amine widely distributed in the CNS, with neurons located in the posterior hypothalamus. HA acts as a neurotransmitter and/or neuromodulator regulating neuroendocrine and neuroimmune functions, circadian rhythms, sleep-wakefulness cycle, body temperature, centrally-mediated neurovegetative functions, cerebrovascular control, and behavior and learning. Changes in brain HA are observed in aging. High levels of HA in CSF and CNS of AD patients might reflect a reactive response to neuroimmune activation and tissue damage.

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.

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.

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.

The topography of the electroencephalographic (EEG) pattern of ten patients with primary degenerative dementia of the Alzheimer type, ten multiinfarct dementia patients, and ten age-matched controls was compared during three different behavioral conditions: resting condition with eyes open (EO), memorizing a list of words (M), and recalling the same list of words (R). Results indicate that the alpha frequency band does not show significant changes. On the other hand, the theta band could be considered an important factor in the differential diagnosis of the primary degenerative dementia of the Alzheimer type, showing a higher power over right posterior regions in this group of patients compared with the multiinfarct dementia patients under different behavioral conditions.

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)

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.

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)

In an attempt to clarify the nature of histaminergic neuromodulation of the vasopressinergic system, several studies under different experimental paradigms were carried out. L-Histidine loads (8 mmol/kg, i.p.) induced a marked increase in histamine (HA) in the anterior (AHR) and posterior (PHR) hypothalamic regions, the median eminence (ME) and adenohypophysis (Ah) with no apparent effect on the concentration of HA in the neurohypophysis (Nh), as measured by high-performance liquid chromatography. These findings correlated with decreases in vasopressin (VP) levels in the AHR and ME, accompanied by increases of the neuropeptide in the PHR and Ah. Intraperitoneal injections of HA (6 mumol/kg), resulted in a significant (p less than 0.005) rise in VP levels in the PHR, ME and Ah. HA induced an elevation of VP in the prefrontal cortex (PFC) from 6.23 +/- 2.02 to 43 +/- 4.05 microU/mg, as well as a 60% reduction in neurohypophyseal VP. These HA-induced VP responses were abolished by both mepyramine (3 mumol/kg) and famotidine (4 mumol/kg) in the PHR and PFC. Mepyramine suppressed the HA-induced VP response in the Ah and enhanced it in the Nh, while famotidine did the opposite. When alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of histidine decarboxylase, was administered at doses of 100 mg/kg/day (i.p.), hypothalamic HA levels fell by 40-45% after 1 h, by 50% after 3 h, and by 65-80% after 24 h in adrenalectomized rats. In the same conditions, but after a week of treatment with FMH, the VP response to adrenalectomy was clearly impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

The concentration of histamine (HA) has been determined by high-performance liquid chromatography (HPLC) with fluorometric detection in 21 different regions of brains from patients with senile dementia of the Alzheimer type (SDAT) and subjects (CB) whose causes of death were not related to neuropsychiatric, neurological and/or neurodegenerative diseases. The highest levels of HA in the central nervous system (CNS) of both control (CB) and SDAT samples were found in the posterior hypothalamus (CB = 3.13 +/- 0.63 pmol/mg; SDAT = 7.75 +/- 1.43 pmol/mg, p less than 0.005), where the HA neurons are located, and in the anterior hypothalamus (CB = 1.77 +/- 0.33 pmol/mg; SDAT = 2.82 +/- 0.45 pmol/mg, p less than 0.005). The lowest HA levels were detected in the cerebellum (CB = 0.12 +/- 0.04 pmol/mg; SDAT = 0.24 +/- 0.09 pmol/mg, p less than 0.01) and medulla oblongata. HA levels were significantly higher in SDAT than in CB in the following areas: motor cortex (Brodmann's area 4) (A4), premotor cortex (A6), postcentral gyrus (A1,2), posterior parietal cortex (A5,7), superior temporal gyrus (A41,42), temporal pole (A38), primary and secondary visual cortices (A17,18), anterior and posterior regions of the hypothalamus, putamen, caudate nucleus, nucleus accumbens, thalamus, hippocampus, pons, medulla oblongata and cerebellum. No changes were seen in globus pallidus and corpus callosum. Since the origin of HA in the brain is dependent upon three main compartments (neuronal, mast cell, vascular smooth muscle), with approximately 60-80% of the total HA belonging to the neuronal pool, on the basis of neurochemical data we postulate that the increase in the levels of HA in SDAT might account for or be associated with alterations in neuroendocrine, cognitive, neurovascular and sleep-wakefulness functions.

The effects of cerebral histamine depletion induced by alpha-fluoromethylhistidine (FMH) on corticotropin (ACTH) and corticosterone secretions were examined. Neither acute nor chronic FMH treatment altered the corticoadrenal responses to three types of stress: transposition, immobilization and water immersion. And exposure to stress did not affect the hypothalamic content of histamine. However, chronic intracerebral treatment with FMH had a significant effect on the circadian rhythm of the plasma corticosterone (CS) level in rats. Namely, it caused a marked attenuation of the amplitude of the peaks of the CS level resulting in an almost arrhythmic state. The maximum differences between FMH treated and untreated groups were seen at 8.00 and 20.00 h, the times when the illumination condition changed (light onset 8.00 h). This treatment with FMH also had a similar effect on the plasma ACTH concentration; namely the plasma ACTH level in the saline treated group was lower than that of the FMH-treated group at light onset and higher than the latter at dark onset, but was similar to the latter at other sampling points. These results indicate the histaminergic modulation of the circadian rhythm of hormonal secretion of the adrenal cortex and show that this phenomenon is mediated through the central nervous system by an influence on the rhythm of hypophyseal ACTH secretion possibly through alteration in the concentration of corticotropin-releasing factor.

To clarify the functional state of the somatotropinergic system at the hypothalamo-hypophyseal level in senile dementia of the Alzheimer type, the GHRH test was performed in three groups of subjects: a) healthy elderly subjects; b) early onset senile dementia patients; and c) late onset senile dementia patients. Intravenous administration of GHRH(1-44)NH2 (100 micrograms) elicited a marked plasma GH response with a maximum peak (709.54 +/- 259.0 pmol/l; P less than 0.005) 60 min after injection in patients with early onset senile dementia, but no significant response was detected in the other two groups. Electroencephalographic recording showed that GHRH modifies brain bioelectrical activity, decreasing frequency (0.52 +/- 0.15 Hz) and increasing amplitude (8.25 +/- 4.5 microV) of the electroencephalogram basic rhythm. The evaluation of mental performance and behaviour with a battery of different tests for mental assessment revealed that GHRH induces transient clinical changes in psychomotor behaviour. According to these results, it seems likely that the somatostatin deficiency reported in senile dementia of the Alzheimer type may account for the enhanced GHRH-induced GH response observed in patients with early onset senile dementia. In consequence, the GHRH test might constitute a useful antemortem marker for senile dementia of the Alzheimer type if the present results can be replicated in early stages of the disease.

Studies on the morphological distribution of histamine (HA)-secreting neurons and their hypothalamic projections suggest that HA may play a key role in regulating neuroendocrine functions, some of which have been recently elucidated. To investigate possible interactions between the somatotropinergic and histaminergic systems in the brain, the effects of GRF-44 [0.1-10 micrograms intracerebroventricular (icv)] and somatostatin (SS-14; 0.1-10 micrograms, icv) on HA in five different parts of the hypothalamo-hypophyseal system, and in the hippocampus and frontal cortex, were studied using a highly sensitive HPLC system for determination of HA. GRF-44 (1 microgram, icv) elicited significant (P less than 0.005) increases in the concentration of HA in the anterior hypothalamus, posterior hypothalamus, median eminence, adenohypophysis, neurohypophysis, frontal cortex, and, to a lesser extent, in the hippocampus, after a clear time-dependent pattern with maxima 15 min after injection. In contrast, SS-14 (1 microgram, icv) significantly (P less than 0.005) decreased the levels of HA in all areas studied, except in the neurohypophysis. The SS-induced HA levels reached minima 30 min after injection. The antagonistic effects of GRF-44 and SS-14 on the release of brain HA were dose dependent, showing an inverse linear correlation within the range 0.1-10 micrograms in the anterior hypothalamus (r = -0.59) and posterior hypothalamus (r = -0.75). Responses of HA to GRF-44 and SS-14 (range: 0.1-10 micrograms) also exhibited an inverse linear correlation in the median eminence (r = -0.90) and adenohypophysis (r = -0.58), while in the hippocampus and frontal cortex the antagonistic effects of GRF and SS displayed an inverse curvilinear correlation. SS-14 ED50 values ranged from 0.6 to 1.75 nmol with Emax of 0.65-6.10 nmol. GRF-44 ED50 values ranged from 0.02-0.3 nmol and the Emax values oscillated between 0.2 and 1.90 nmol in the regions studied. The greatest responses of HA to GRF-44 and SS-14 were obtained in the hypothalamo-hypophyseal system. Although brain HA is present in both the neuronal and the mast cell compartments, changes induced in the concentration of HA by centrally administered GRF-44 and SS-14 appear to occur mostly in the neuronal compartment. Therefore, it is likely that the somatotropinergic and histaminergic systems reciprocally interact at the central level to regulate still unknown neuroendocrine functions.

Administration of hypothalamic peptides has been reported to induce behavioral changes and to modify neurological functions such as locomotor activity and learning. Somatostatin (SS) and growth hormone-releasing factor (GRF) exert opposite effects on anterior pituitary secretion. Similarly, at the central nervous system (CNS) level, SS and GRF display antagonistic actions on behavioral parameters. The authors were able to confirm these effects in male Wistar rats by means of a computerized electronic maze measuring locomotor activity and learning. SS concentration is reduced in specific areas of the CNS in patients with late onset of senile dementia of the Alzheimer's type (SDAT). In early onset SDAT a GRF test elicits a growth hormone response much greater than that observed in normal controls of the same age or in patients with late onset SDAT. Thus, administration of GRF to patients with early onset SDAT has been followed by a significant improvement in locomotion, appetite, mental performance and social interaction. A possible therapeutic role of GRF in the management of patients with dementia remains to be explored.

Changes in the level of histamine (HA) in rat brain induced by intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administrations of growth hormone-releasing factor (GRF1-44) were studied. HA was determined by high-performance liquid chromatography (HPLC) in the anterior hypothalamic region, posterior hypothalamic region, median eminence, adenohypophysis, neurohypophysis, hippocampus and prefrontal cortex. GRF1-44 (1-10 micrograms, i.c.v.) induced significant time- and dose-dependent increases in the concentration of HA in the hypothalamo-hypophyseal system and time-dependent decrease of HA in the hippocampus. In contrast, after i.p. administration of GRF1-44 (10 micrograms) the level of HA in the hypothalamus tended to decrease but the total amount of H-1 receptors in the hypothalamo-hypophyseal system did not change. Circadian variations in the GRF-induced HA and growth hormone responses were also observed, responses being lower in the evening than in the morning. It is concluded that GRF interacts with HA at the central level to optimize the function of the somatotropinergic system.

The effects of somatostatin (SS-14) (0.1-10 micrograms, i.c.v.) on brain histamine (HA) in male Wistar rats were investigated. HA was measured by HPLC with a cation exchanger and an automated fluorometric detection system. SS-14 induced time- and dose-dependent changes in the levels of HA in the anterior hypothalamus, posterior hypothalamus, median eminence, adenohypophysis, hippocampus, and frontal cortex. In the anterior hypothalamus, posterior hypothalamus and hippocampus, SS-14 (1 microgram, i.c.v.) significantly (p less than 0.01) decreased the levels of HA from 5 to 30 min. This response was delayed by 5 min in the frontal cortex and adenohypophysis. Only in the neurohypophysis, SS-14 increased the concentration of HA 10 min after injection, but this response was not dose-related. These results seem to indicate that SS-14 influences neuronal HA probably modifying HA release, it leading to a decrease of the levels of the biogenic amine in specific areas of the brain. Since this effect is opposite to that developed by growth hormone-releasing factor (GRF) in identical conditions, HA seems to fulfil the criteria by which a neuroendocrine modulator should currently respond in a specific time- and dose-dependent manner to those neuropeptides which modulate. Therefore, HA is likely to play a key role as a neuromodulator of the somatotropinergic system in the rat.