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Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 73 records · Page 4Linked to original sources
PubMed1989

Facilitation of calcium-dependent cholinergic function by ucb L059, a new "second generation" nootropic agent.

We have investigated the effect of piracetam (PIR) and of its structural analogs, ucb L059 and ucb L060, the optical isomer of ucb L059, on cholinergic function in the guinea pig ileum in vitro. Only ucb L059 (10 microM-10 mM) caused contraction of the ileal preparation in a dose-dependent manner. This effect was inhibited by atropine (greater than or equal to 3.2 nM), by tetrodotoxin (10 nM) and by a combined treatment of veratridine (50 nM) and hemicholinium-3 (HC-3;0.5 mM), and was potentiated by physostigmine (50 nM). Electrically evoked contractions (EEC) of guinea pig ileal preparations subjected to HC-3 (0.5 mM) followed by veratridine (50 microM) were suppressed due to depletion of acetylcholine. Choline (greater than or equal to 3.2 10(-7)M) and ucb L059 (0.1-10 mM), but not ucb L060, facilitated recovery of EEC in a dose-dependent manner. This effect was abolished by HC-3. In addition, twitch recovery was inversely related to the concentration of Ca+2 in the medium. These results indicate that ucb L059, a close structural analog of piracetam, appears to facilitate cholinergic function in vitro through a stereospecific mechanism.

Animals↗
PubMed1988

AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates.

The present studies examined the behavioral, neurochemical and histological consequences of intraventricular administration of ethylcholine aziridinium ion (AF64A). Male Long-Evans rats were trained to perform a radial arm maze task in which a one hour delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were bilaterally injected with AF64A (3 nmol/side) or CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. AF64A-treated animals were markedly impaired in their ability to perform this working/episodic memory task at a variety of delay intervals. In contrast to a long-lasting impairment on the radial maze task, these animals showed no impairment in their ability to acquire a simple discrimination task (reference/skill memory). Neurochemical analysis revealed a significant (50%) decrease in choline acetyltransferase (ChAT) activity in the hippocampus (HPC) 90 days following surgery. ChAT activity was not affected in the striatum, frontal and parietal cortices, cingulate or amygdala. Regional concentrations of catecholamines and indoleamines were not affected in any of these brain regions. Histological analysis of animals receiving unilateral injections of AF64A (3 nmol) into the right lateral ventricle revealed decreases in ChAT-immunoreactive (ChAT-IR) cells within the medial septum/vertical limb diagonal band (MS/VLDB), but not in nucleus accumbens, striatum or basal nucleus regions. These data suggest that: (1) intraventricular administration of AF64A can markedly impair working/episodic, as opposed to reference/skill memory, processes; (2) AF64A can be used to selectively alter presynaptic cholinergic indices within the hippocampus; and (3) the behavioral deficits resulting from AF64A administration are most likely a consequence of altered septohippocampal cholinergic function.

Animals↗
PubMed1988

Bilateral symmetry of cholinergic deficits in Alzheimer's disease.

The specific activities of the cholinergic enzymes, choline acetyltransferase and acetylcholinesterase, as well as the density of muscarinic binding sites, were determined in five corresponding left and right regions of 16 brains obtained at autopsy from patients with histologically confirmed Alzheimer's disease. While a significant proportion of the individual specimens exhibited left-right asymmetries in cholinergic deficits, bilateral symmetry was the rule for frontal and temporal cortex, basal nucleus, and the prosubiculum of the hippocampus. In contrast to these four regions, left-right asymmetries in choline acetyltransferase activity and muscarinic receptor density appeared to be typical in the entorhinal cortex of the hippocampus.

Acetylcholinesterase↗
PubMed1988

Cerebrospinal fluid and urinary biogenic amines in depressed patients and healthy controls.

The National Institute of Mental Health-Clinical Research Branch Collaborative Study investigated 132 drug-free, severely depressed patients and 80 healthy controls. Forty-five percent of the depressed patients excreted markedly elevated levels of urinary epinephrine (E) and metanephrine (MET), while only 5% of healthy controls did so. Using gaussian mixture distributions, we identified two subgroups of depressed patients: one excreting normal levels and the other excreting high levels of urinary E, MET, norepinephrine, and normetanephrine. Cerebrospinal fluid homovanillic acid levels were low in a subgroup of depressed patients. When analyzed by subgroup, the elevated E + MET group had markedly lower cerebrospinal fluid homovanillic acid levels than controls, whereas depressed patients with normal catecholamine levels did not. Since it has been postulated that there are two subgroups of depressed patients, those with low 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and normal 5-hydroxyindoleacetic acid (5-HIAA) levels and those with normal MHPG levels and low 5-HIAA levels, several analyses were performed to see if such a group could be identified. Our analysis failed to find evidence of a subgroup of depressives with low MHPG and normal 5-HIAA levels or normal MHPG and low 5-HIAA levels.

Biogenic Amines↗
PubMed1988

Formation and degradation of 1-(ethyl)-1-(2-hydroxyethyl) aziridinium chloride in aqueous media--a comparative NMR study.

The formation and decomposition of 1-(ethyl)-1-(2-hydroxyethyl) aziridinium chloride in aqueous media (10 mM solutions) was studied by NMR spectroscopy. Compared to 1-diethyl aziridinium chloride which lacks the hydroxyl group, the degradation of the title compound at 37 degrees C and pH = 7.4 is about 10 times faster. However, liquid nitrogen frozen solutions of both aziridinium salts are stable for long periods of time (1-6 months).

Aziridines↗
PubMed1988

Role of the aziridinium moiety in the in vivo cholinotoxicity of ethylcholine aziridinium ion (AF64A).

To assess the role of the aziridinium moiety for the cholinotoxicity of ethylcholine aziridinium ion (AF64A) we compared in vitro and in vivo effects of AF64A with those of various precursors as well as decomposition products of AF64A. In vitro, AF64A was the most effective irreversible inhibitor of high-affinity choline transport (HAChT) in hippocampal synaptosomes. The uncyclized precursor acetylethylcholine mustard and the acetylated form of AF64A were about 3 times less potent. Their potency, however, was reduced considerably when hydrolysis of the choline esters was prevented by physostigmine. Destruction of the aziridinium ring either by high pH (alcohol formation) or by thiosulfate (formation of Bunte salt) resulted in a loss of biological activity. This was also the case for the in vivo cholinotoxicity, as assessed by the decline in hippocampal concentration of acetylcholine (ACh) 7 days after intracerebroventricular (i.c.v.) infusion. The most pronounced reduction in ACh content was achieved after i.c.v. infusion of AF64A, whereas the precursor and the acetylated analog of AF64A induced a significant, but smaller reduction in the ACh content. These data indicate that the aziridinium ring of AF64A is essential for both the inhibition of HAChT in vitro and the cholinotoxicity in vivo. However, cyclization of the precursor compound as well as hydrolysis of acetylated AF64A also occur in tissue, leading to a partial activity of these compounds.

Animals↗
PubMed1988

Red blood cell/plasma choline ratio in elderly depressed and demented patients.

In further study of red blood cell (RBC) and plasma choline concentrations in 160 elderly subjects, we found no significant differences in RBC/plasma choline ratios among depressed, demented, and healthy subjects. On the basis of a smaller sample, we had earlier reported that a significantly higher proportion of Alzheimer patients had RBC/plasma choline ratios greater than 1.9. Thus, it now appears that static RBC choline levels cannot be recommended as a specific marker of Alzheimer's dementia. However, within subgroups of these diagnostic categories, determined by RBC/plasma choline ratios less than or equal to 1.9 or greater than 1.9, consistent differences in electroencephalographic (EEG) sleep measures were found. The subgroup of demented patients with a RBC/plasma choline ratio greater than 1.9 was more impaired on the Blessed Dementia Rating Scale and had less rapid eye movement (REM) sleep than the subgroup with a choline ratio less than or equal to 1.9. Similarly, depressives with a choline ratio less than or equal to 1.9 had a lower REM latency than depressives with a choline ratio greater than 1.9. Finally, depressed-demented (i.e., mixed-symptom) patients with a choline ratio greater than 1.9 showed less sleep continuity disturbance but more indeterminate non-REM sleep (reflecting loss of spindles and K-complexes) than those with lower choline ratios. These differences parallel those previously reported for diagnostically "pure" depressed and demented patients, and they suggest a possible link between peripheral RBC/plasma choline measures and central nervous system function as reflected in sleep physiological alterations.

Aged↗
PubMed1987

Effect of cholinergic deficit induced by ethylcholine aziridinium (AF64A) on noradrenergic and dopaminergic parameters in rat brain.

The consequences of reduced cholinergic function on noradrenergic and dopaminergic neurons has been studied in various rat brain areas for a period of up to 28 days following bilateral intracerebroventricular infusion of various doses of ethylcholine aziridinium ion (AF64A; 1-5 nmol/ventricle). This treatment resulted in a dose-dependent, persistent decrease in acetylcholine (ACh) content ranging from 50.3 +/- 6.0% to 76.9 +/- 3.8% when compared to vehicle-injected rats. Concomitantly, there was a transient, dose-dependent decrease (up to 46.7 +/- 6.4%) in norepinephrine (NE) levels in hippocampus, cortex and hypothalamus. Whereas the noradrenergic system recovered fully within 28 days after 1-3 nmol AF64A/ventricle, the decrease in NE levels persisted after 5 nmol/ventricle. In striatum, a small decrease in ACh levels 4 days after AF64A infusion was accompanied by a transient, dose-dependent decrease in the levels of dopamine (DA) and its metabolites dihydroxyphenylacetic acid and homovanillic acid, suggesting a decrease in DA synthesis and release. Dopaminergic function was fully restored within 14 days after all doses of AF64A used. These data suggest that reduction of cholinergic function might have a considerable impact on noradrenergic and dopaminergic neurons, causing an increase in NE release as well as depression of dopaminergic function.

Acetylcholine↗
PubMed1987

AF64A (ethylcholine aziridinium ion), a cholinergic neurotoxin, selectively impairs working memory in a multiple component T-maze task.

The present study examined the nature of the cognitive deficits associated with a selective decrease of cholinergic activity in the hippocampus. Male Fischer rats were trained to perform a multiple component T-maze task which simultaneously assessed their ability to perform on the basis of trial-specific information (working memory) and trial-independent information (reference memory). Following 125 acquisition trials rats were bilaterally injected with AF64A (3 nmol/side) or artificial CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. The controls rapidly returned to their preoperative level of performance on both components of the maze task. AF64A-treated animals were transiently impaired on the reference memory task. Their performance rapidly improved and they were performing at preoperative levels within 4 days of testing. In contrast, these animals exhibited a marked and long-lasting impairment in their performance of the working memory component. After behavioral testing was completed, neurochemical analysis revealed that AF64A produced a significant decrease in choline acetyltransferase (ChAT) activity in the hippocampus (43%) 42 days following surgery. This dosing regimen produced no alterations of striatal or cortical ChAT activity. These data suggest that alterations of hippocampal cholinergic activity severely impair an animal's ability to perform working memory tasks.

Animals↗
PubMed1987

Thalamic and subcortical gliosis with dementia.

We describe two cases of patients with "primary dementia" in whom autopsy showed marked astrocytosis in several subcortical nuclei, but chiefly in those of the thalamus. One patient had the onset of symptoms at 31 years of age and a subacute course. The second patient was an elderly man with a strong familial history of dementia. These cases offer further evidence that subcortical lesions, especially in the thalamus, may produce a dementia that is not always clinically distinguishable from Alzheimer's disease and other "cortical" dementias.

Adult↗
PubMed1987

Changes in urinary catecholamines and their metabolites in depressed patients treated with amitriptyline or imipramine.

The effects of treatment with amitriptyline (AMI) or imipramine (IMI) on changes in catecholamines and their metabolites in urine were studied in 95 unipolar and bipolar depressed patients. For the entire group, not separated by drug, substantial reduction in concentrations of all metabolites, but not catecholamines, occurred. Although catecholamine and metabolite change was similar for most substances assayed, there were some specific drug and diagnostic group differences. Vanillylmandelic acid (VMA) reduction was limited to bipolar patients; metanephrine (M) reduction to unipolar patients. Greater M and 3-methoxy-4-hydroxyphenylglycol (MHPG) reduction were associated with response in unipolar, but not bipolar patients. In bipolar, but not unipolar patients, norepinephrine (NE) rose in responders in contrast to reductions among nonresponding bipolar patients. The results suggest that effectiveness of blockade of reuptake of norepinephrine may be relatively more important for recovery in bipolar than in unipolar patients. Study of a battery of amine substances may contribute more information to our understanding of antidepressant drug effects on aminergic systems than analyses of MHPG alone.

Adult↗
PubMed1987

Time course of ethylcholine aziridinium ion (AF64A)-induced cholinotoxicity in vivo.

The time course of the cholinotoxicity of ethylcholine aziridinium ion (AF64A) has been investigated. Rats were injected with AF64A (3 nmols/3 microliters/side, bilateral, i.c.v.) or with vehicle. One day to one year after treatment, the hippocampus, cortex and striatum were analyzed for the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) and high-affinity transport of choline (HAChT). In addition, the release of K+-stimulated acetylcholine (ACh) from superfused slices of hippocampus was determined. The first parameter affected was high affinity transport of choline. One day after treatment with AF64A, the high affinity transport of choline in the hippocampus was reduced by 23%. This reduction was maximal one week after treatment (-67%) and persisted for at least 6 months. The high affinity transport of choline in the striatum and cortex was not altered by treatment with AF64A. The activity of ChAT and AChE in the hippocampus was reduced by 2 days after treatment with AF64A. These deficits persisted for at least 6 months (AChE) to 1 year (ChAT). The activity of ChAT and AChE in the cortex and striatum was minimally affected up to 1 year after treatment with AF64A, at which time significant reductions were noted. The release of ACh was affected 3 days after treatment with AF64A, and remained attenuated 6 months later. These data indicate that the cholinergic deficit caused by in vivo treatment with AF64A was first apparent at the level of high affinity uptake of choline in the hippocampus HAChT. Subsequently, the activity of ChAT and AChE and release of ACh in the hippocampus were affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1987

Hippocampal electrical activity in relation to behavior following ethylcholine aziridinium ion (AF64A) treatment.

The effects of intracerebroventricular (ICV) injections of ethylcholine aziridinium ion (AF64A; 3 nmol/3 microliters/side) on the pattern of hippocampal electrical activity were studied in freely moving and urethane anesthetized rats. AF64A treated rats showed a significantly smaller increase in 6-12 Hz hippocampal rhythmical slow activity (RSA) with struggling in the no drug condition in comparison to the vehicle injected rats. However, neither AF64A treatment nor a control injection abolished the presumed cholinergic form of RSA that is present during urethane anesthesia. Systemic injection of atropine in waking rats did not significantly alter RSA in either the AF64A or vehicle injected rats. Analysis of histological brain sections revealed extensive damage to the fimbria-fornix, CA3 of the hippocampus, corpus callosum, neocortex and striatum. Acetylcholinesterase staining of the remaining hippocampus appeared normal in the AF64a treated rats. The data indicate that the depletion of cholinergic markers in the hippocampus following ICV administration of AF64A is not sufficient to disrupt the cholinergic form of RSA. Further, the question is discussed as to whether AF64A produces its cholinoselective effects via a specific pharmacological action or through a nonspecific destruction of the fimbria-fornix.

Animals↗
PubMed1987

Stimulation of cell membrane sodium transport activity by lithium: possible relationship to therapeutic action.

Because lithium is extruded from cells by means of coupled exchange for external sodium (Na+-Li+ countertransport), we hypothesized that clinical treatment with this agent could lead to significant augmentation of net cellular sodium influx. We therefore directly measured sodium influx in vitro using erythrocytes (RBCs) from 27 depressed bipolar patients. When cells were loaded with sufficient lithium to maximally stimulate Na+-Li+ countertransport activity (5.1 mmoles/1 RBCs), there was a significant 44% increase in mean sodium influx. To approximate clinical conditions more closely, we also studied sodium influx in a subset of eight subjects after loading cells with 0, 0.40, 0.66, and 1.55 mmoles lithium/1 RBCs. Over this range of lithium concentrations, sodium influx increased progressively. In separate experiments, we found that RBC sodium content measured in eight subjects did not change significantly during a 4-week course of lithium treatment. Thus, excess cellular sodium during such treatment may be extruded by increased activity of the membrane Na+-K+ pump, which has electrogenic properties and thereby could augment the membrane potential. In the nervous system, such an effect could stabilize cell membranes electrophysiologically, and possibly affect processes, such as behavioral sensitization or kindling, proposed to have a role in the development of recurrent affective disorders.

Bipolar Disorder↗
PubMed1987

Effect of cholinergic deficit induced by ethylcholine aziridinium on serotonergic parameters in rat brain.

The consequence of loss of cholinergic input on the function of serotonergic neurons has been studied in rat brain after bilateral intracerebroventricular injections of various doses of the cholinotoxin ethylcholine aziridinium ion (1 to 5 nmoles/ventricle). This treatment resulted in a dose-dependent decrease in acetylcholine content in hippocampus, which occurred 2 days after injection and persisted during the 28 day observation period. The reduction in acetylcholine content ranged from 50.3 +/- 6.0% to 76.9 +/- 3.8% when compared to vehicle-injected rats. Other brain areas, including cortex, striatum and hypothalamus, showed only minor and transient changes in acetylcholine levels. Treatment with ethylcholine aziridinium was accompanied by a dose-dependent response of serotonergic neurons. The predominant reaction, which we observed in all areas studied, was an initial increase in 5-hydroxyindoleacetic acid content, a decrease in serotonin content, and consequently an increase in the molar ratio of metabolite/amine, indicating an increase in serotonin turnover. As with acetylcholine, the decrease in serotonin content was most pronounced in the hippocampus, ranged from 19.4 +/- 2.9% to 53.4 +/- 4.1%, and even persisted at 28 days after injection of 3 and 5 nmoles of the toxin/ventricle, although serotonin levels returned towards normal at that time point after injection of 1 or 2 nmoles of the toxin/ventricle. These data suggest that, in the rat, withdrawal of cholinergic input to the hippocampus might have a considerable impact on serotonergic function. This includes an initial increase in activity and, as cholinergic degeneration progresses, a decrease in serotonergic function. The most likely explanation for the serotonergic deficit is that it may reflect adaptation of these neurons to the withdrawal of cholinergic input. Such a phenomenon might help to increase our understanding of the events taking place in the brains of patients with Alzheimer's disease as the cholinergic system starts to degenerate.

Acetylcholine↗
PubMed1986

Acute in vivo exposure to ethylcholine aziridinium (AF64A) depresses the secretion of quanta from motor nerve terminals.

Quantal release of acetylcholine was evaluated for soleus nerve-muscle preparations removed from mice treated with the cholinergic neurotoxin AF64A. Treatment with two and three times the LD50 (i.p.) of AF64A caused a marked reduction of the frequency of miniature end-plate potentials (mepps) and the amplitude of end-plate potentials (epps). Since the amplitude of mepps was not altered, the reduction of epps was not due to reduction in the number of molecules of acetylcholine (ACh) per quantum or the end-plate sensitivity to ACh, but to a reduction of the number of quanta released in response to a nerve action potential. While this effect was not reversed when preparations were washed for 3 h, exposure to the potassium channel blocker, 3,4-diaminopyridine returned the mean quantal content of epps to normal. These data further support a presynaptic site of action for AF64A, and suggest that it may acutely disrupt the ionic processes underlying transmitter release.

Acetylcholine↗