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Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 55 records · Page 3Linked to original sources
PubMed1991

Erythrocyte choline concentrations in psychiatric disorders.

Erythrocyte choline has been used as a potential indirect measure of cholinergic function in the central nervous system (CNS). We review the literature and present some new data on erythrocyte choline concentrations in patients with neuropsychiatric disorders. Our data and most of the reviewed studies report modest elevations in mean erythrocyte choline values in patients with affective illnesses, psychoses, dementia, and other neuropsychiatric disorders when compared to controls. Within each disorder, the increased mean erythrocyte choline concentrations are due to subgroups of patients with especially high values. These subgroups of patients with elevated erythrocyte choline levels appear to have clinical characteristics that distinguish them from patients with normal choline values. Finally, the dramatic rise in erythrocyte choline concentration produced by lithium therapy is reviewed, and the implication of this effect, in particular, the possibility that pretreatment or posttreatment erythrocyte choline concentrations may predict response to lithium, is discussed.

Adult↗
PubMed1991

The cholinergic-adrenergic hypothesis of depression reexamined using clonidine, metoprolol, and physostigmine in an animal model.

The role of central nervous system (CNS) cholinergic and noradrenergic mechanisms in the pathogenesis of depression and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is examined using the Behavioral Despair rat model of depression. Immobility (IM), the analog of depression in this model, and plasma corticosterone (C) were increased by physostigmine (PHYSO). Neostigmine (NEO), which does not cross the blood-brain barrier, produced the same peripheral cholinomimetic effects and motor inhibition as PHYSO, but did not change IM. PHYSO's effects on C and IM were blocked by metoprolol pretreatment and partially blocked by clonidine pretreatment. PHYSO increased acetylcholine in the striatum. In this animal model of depression, cholinergic and noradrenergic mechanisms are interactively involved in the regulation of behavioral depression and the HPA axis.

Acetylcholine↗
PubMed1991

Acute and chronic studies with the anticholinesterase Huperzine A: effect on central nervous system cholinergic parameters.

High affinity choline transport, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) were assessed in rats after acute and chronic administration of the AChE inhibitor Huperzine A. Acute treatment: Forty-five min after a single injection of Huperzine A (0.5 mg/kg i.p.) the activity of AChE was significantly decreased by 15-30% in hippocampus, striatum and septum. The activity of ChAT was not altered. In the hippocampus high affinity choline transport was attenuated by 25%, whereas no effect in the striatum was observed. After 90 min, both inhibition of AChE and attenuation of high affinity choline transport had returned to control values. A dose of 0.1 mg/kg (i.p.) did not produce significant effects. Similar results were obtained with physostigmine (0.25 mg/kg), although the duration of inhibition of AChE was shorter than that with Huperzine A. Chronic treatment: After 5 days (twice a day), at 0.5 mg/kg, the activity of AChE was significantly reduced by 20-30% in every region of the brain studied. High affinity choline transport in the hippocampus was reduced by 28%, 45 min after the last injection, but in the striatum there was no effect. The activity of ChAT was not affected in any region of the brain studied. Thus, acute or chronic treatment with Huperzine A: did not alter ChAT; reduced high affinity choline transport in the hippocampus in a transient manner; and had a longer duration of action as an AChE inhibitor than physostigmine. Moreover, tolerance to low-toxicity doses of Huperzine A was minimal, contrary to what has been observed with other inhibitors of AChE.

Acetylcholinesterase↗
PubMed1991

Septal choline acetyltransferase immunoreactive neurons: dose-dependent effects of AF64A.

Two experiments were performed. In the first, the cholinotoxin, AF64A (0.5, 1.0 or 1.5 nmol/ventricle), or vehicle (3.0 microliters) was injected (ICV) bilaterally into male rats (n = 23). Choline acetyltransferase (ChAT) immunoreactive (IR) perikarya in the four subgroups of the septal complex were visualized by immunocytochemistry (PAP method) 28 days postinjection, and counted using a microprojector (x40). The 0.5 nmol/ventricle dose of AF64A significantly reduced (31%) the number of ChAT-IR cell bodies in the intermediate subgroup (rostral extension of the nucleus basalis/substantia innominata). Higher doses did not produce additional reductions. The highest dose (1.5 nmol/ventricle) of AF64A resulted in significant decreases in ChAT-IR cell bodies in the dorsal (51%) and midline (35%) subgroups (medial septum), but did not affect the number of ventral subgroup (diagonal band of Broca) ChAT-IR neurons. In the second experiment, electrolytic lesions were placed in the corpus callosum, cingulum and overlying cingulate gyrus, in order to simulate the nonselective damage seen following the 1.5 nmol/ventricle dose of AF64A. In comparison to the surgical controls (n = 3), the electrolytic lesions (n = 6) failed to significantly affect the number of ChAT-IR perikarya in any of the septal subdivisions. Thus the distinct subgroups of septal ChAT-IR neurons are differentially sensitive to the toxic effects of ICV administered AF64A: intermediate much greater than dorsal greater than midline much greater than ventral subgroup.

Animals↗
PubMed1991

Neurochemistry of aging. 2. Design, synthesis, and biological evaluation of halomethyl analogues of choline with high affinity choline transport inhibitory activity.

The design, synthesis, and testing of several halomethyl analogues of choline and acetylcholine as potential cholinotoxins is described. The compounds were evaluated for their ability to inhibit high-affinity choline transport and their affinity toward postsynaptic muscarinic receptors. Among the analogues tested, bromomethyl and iodomethyl analogues of choline were found to be the most potent inhibitors of the high affinity choline transport system. Introduction of a beta-methyl group in the halomethyl analogues drastically reduced their potencies. The bromomethyl and iodomethyl analogues were further investigated for their effects on choline acetyltransferase activity, acetylcholinesterase activity and QNB binding. Neither compound possesses significant ability to alter any of the above cholinergic markers, except at very high concentrations. These results suggest that the bromomethyl and iodomethyl choline analogues may be used as specific inhibitors of the presynaptic high-affinity choline transport system.

Acetylcholinesterase↗
PubMed1990

Lumbar cerebrospinal fluid choline in healthy aging and in Down's syndrome.

Choline concentrations were measured in lumbar cerebrospinal fluid (CSF) and plasma of 37 healthy normal subjects and 13 young (age range, 21 to 34 years) and 6 older (age, greater than or equal to 45 years) healthy adults with Down's syndrome (DS). All subjects with DS had a trisomy 21 karyotype, and 3 of the 6 older subjects were demented as judged from a history of mental deterioration, disorientation, and memory loss. In healthy normal subjects, there was a significant correlation between age and CSF choline concentrations. Compared with age-matched controls, in young subjects with DS, CSF, but not plasma, choline concentrations were elevated (by 49%), whereas in older subjects with DS, CSF and plasma choline concentrations were similar to control values. The CSF choline concentrations were unrelated to body height in the DS and control groups, and rostrocaudal CSF choline gradients did not differ between either the control and DS groups or the young and old subjects with DS, suggesting that the elevation in the CSF choline concentration in young subjects with DS was not related to their shorter stature. Since increased CSF choline concentrations in young adult subjects with DS were accompanied by normal plasma choline concentrations, these results suggest that young adults with DS have either an increased release of choline from the brain or a reduced rate of clearance of choline from CSF.

Adult↗
PubMed1990

Sector-dependent neurotoxicity of ethylcholine aziridinium (AF64A) in the rat hippocampus.

The present study was aimed at measuring the distribution of ethylcholine aziridinium (AF64A)-induced cholinotoxicity within the hippocampus 6 days after bilateral (icv) administration of 1, 2 or 3 nmol, or vehicle. The dissected hippocampus was sectioned with a vibratome into 5 parallel sectors distributed along its long axis from its thalamic surface (medial) to its cortical surface (lateral). In vehicle-treated rats, the high affinity cholinergic transport (HAChT), choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were distributed according to a gradient of increasing activity, extending from the lateral to the medial surface of the hippocampus. After treatment with AF64A, the normal gradient of enzyme activity was profoundly disrupted at all doses of AF64A and the core sectors of the hippocampus were significantly more affected than the superficial sectors. The HAChT gradient was progressively abolished with increasing doses of toxin, and the effect was maximal at 2 nmol.

Acetylcholinesterase↗
PubMed1990

Plasma corticosterone is increased and correlated with brain acetylcholine in physostigmine- but not in neostigmine-treated rats.

Rats were given intraperitoneal injections of physostigmine (PHYSO), neostigmine (NEO) or saline (SAL). Either 15 or 30 min later the number and intensity of observable cholinomimetic effects (OCE) was determined, plasma was collected for corticosterone (Cst) measurement, and the cerebral cortex, striatum, hippocampus and hypothalamus were removed after microwave treatment for the measurement of tissue acetylcholine (ACh) and choline (Ch) concentrations. Plasma Cst correlated with the number of OCEs at both 15 and 30 min in both NEO- and PHYSO-treated animals. Although the number and intensity of OCE were the same in NEO- and PHYSO-treated animals 15 min after injection, plasma Cst was significantly higher in the PHYSO-treated group. ACh levels in the cortex were also increased in PHYSO- compared with NEO-treated animals 15 min after injection. Ch levels remained unchanged. Plasma Cst correlated positively with ACh levels in the cortex and striatum in PHYSO-treated rats both 15 and 30 min after injection. These data support the involvement of central cholinergic mechanisms in the regulation of the HPA axis.

Acetylcholine↗
PubMed1989

Cholinergic and noradrenergic toxicity of intraventricular aluminum chloride in the rat hippocampus.

The effects of the intraventricular administration of aluminum chloride (AlCl3) on high affinity choline transport (HAChT) and norepinephrine concentration were examined in the hippocampus of the rat. Controlling for osmolarity and pH, the intraventricular administration of AlCl3 resulted in a dose-related reduction in both variables with relative selectivity for HAChT. Moreover, the neurotoxicity of intraventricular aluminum appeared to be dependent on the forms of the aluminum salt administered.

Aluminum↗
PubMed1989

Behavioural and histological effects of low concentrations of intraventricular AF64A.

The effects of ethylcholine mustard aziridinium ion (AF64A; 0.3, 1.0 and 3.0 nmol), injected into each lateral ventricle in the rat, were determined in a range of behavioural tests, each involving a learning component. Effects were observed at 1.0 and 3.0 nmol/side and, to a lesser extent, at 0.3 nmol/side. Habituation of locomotor activity was impaired and deficits in learning were obtained using a variety of mazes including the Morris swimming maze. Slight, non-significant impairments occurred in shock reinforced behaviours. Histologically, marginal effects were observed at 0.3 nmol/side, and slight ventricular dilatation with necrosis of the hippocampus, restricted to the site of injection at 1.0 nmol/side; at 3.0 nmol/side more widespread necrosis was apparent. Biochemical efficacy of the lesions in terms of cholinergic changes was confirmed by analysis of acetylcholinesterase (AChE) levels showing decreases in the hippocampus and the cortex; no studies were carried out with respect to other neurotransmitters. Cognitive deficits can therefore be obtained by i.c.v. injection of AF64A at doses which cause significant cholinergic changes with minimal histological disturbances.

Animals↗
PubMed1989

Inhibition of high affinity choline transport attenuates both cholinergic and non-cholinergic effects of ethylcholine aziridinium (AF64A).

Ethylcholine aziridinium (AF64A) has been proposed as a specific cholinergic neurotoxin. In earlier studies, using AF64A, we reported that slow infusion of 1-2 nmol of this compound into each lateral ventricle of Sprague-Dawley rats resulted in small, and transient decreases in noradrenaline (NA) and serotonin (5-HT) levels in the hippocampus, while inducing a permanent and significant cholinergic hypofunction in the same brain region. The experiments described in this paper were designed to test the hypothesis that such noradrenergic and serotonergic changes after small doses of AF64A are secondary to the changes observed in cholinergic neurons. Levels of NA, and of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were measured concurrently with levels of acetylcholine (ACh), in various brain regions of rats in which the effect of AF64A was attenuated, and in respective control animals. The effect of AF64A was diminished by inhibiting the interaction of AF64A with the high affinity transport site for choline (HAChT). This was achieved using hemicholinium-3 (HC-3), which does not cross the blood-brain barrier, and A-4 (a bis 4-methylpiperidine analog of HC-3), which is centrally active following its peripheral administration. A-4 (20 or 40 mg/kg i.p.) or HC-3 (10 micrograms/ventricle) had no effect on ACh, NA, 5-HT or 5-HIAA levels in saline-treated rats. However, all treatments significantly attenuated the decrease in ACh content produced by AF64A pretreatment. Transient decreases in NA, 5-HT and 5-HIAA contents after AF64A treatment were prevented or reduced by prior treatment with A-4 or HC-3. These results indicate that changes in noradrenergic and serotonergic neurons following AF64A administration are not due to non-specific toxicity of AF64A, but may be the result of adaptation of these neurons to withdrawal of cholinergic input, which would normally inhibit the release of NA and 5-HT. These results also indicate that AF64A can be used to produce specific lesions of hippocampal cholinergic nerve terminals.

Animals↗
PubMed1989

A brain regional analysis of morphologic and cholinergic abnormalities in Alzheimer's disease.

In the brains of 21 patients with Alzheimer's disease (AD) and 10 nondemented controls, senile plaques (SPs), neurofibrillary tangles (NFTs), and three indexes of cholinergic function were quantified in the middle frontal (MF) and superior temporal (ST) cortex, the entorhinal cortex (HEN), and the prosubiculum (HPR) of the hippocampus. Control brains contained few SPs without preferential distribution in any of the brain regions examined, while NFTs were found almost exclusively in the HPR. In brains from patients with AD, an inverse relationship of SPs and NFTs was found in the brain regions examined; SPs were preferentially in the neocortex and NFTs preferentially in the hippocampus. The specific activities of choline acetyltransferase and acetylcholinesterase were reduced in all regions examined, while no significant change in the density of muscarinic binding sites was observed in any region. Numerous NFTs were associated with an earlier age at onset, while the presence of SPs was related to the cholinergic deficit in AD. Earlier-onset (less than 67 years) AD was also associated with a qualitative difference in the regional distribution of NFTs compared with cases with a later onset. In the latter group, most NFTs were observed in the hippocampus, a distribution pattern similar to that observed with normal aging. In AD cases with an earlier onset, NFTs were more globally distributed in the neocortex and allocortex.

Acetylcholinesterase↗
PubMed1989

Lateralization of brain morphologic and cholinergic abnormalities in Alzheimer's disease.

The extent of left-right asymmetry in the densities of senile plaques and neurofibrillary tangles and the levels of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase were quantified in the middle frontal and superior temporal cerebral cortex, entorhinal cortex, and prosubiculum of the hippocampus from 21 patients who died with Alzheimer's disease. Morphologic lesions were more asymmetrically distributed than deficits in the cholinergic enzymes. Neither cerebral hemisphere showed consistently higher densities of senile plaques and neurofibrillary tangles, or lower levels of choline acetyltransferase and acetylcholinesterase. Deficits in the cholinergic enzymes tended to colateralize, while asymmetries of senile plaques and neurofibrillary tangles did not. Finally, left-right asymmetry in the density of senile plaques diminished with increasing neuropathologic severity, while similar evidence for diminishing left-right asymmetry of neurofibrillary tangle density or cholinergic enzyme activity with increasing severity was not found.

Acetylcholinesterase↗
PubMed1989

Noradrenaline depletion protects cholinergic neurons in rat hippocampus against AF64A-induced damage.

The role of the noradrenergic system in the cholinotoxicity of ethylcholine aziridinium ion (AF64A) was studied in rats. Male Sprague-Dawley rats were treated with the noradrenergic neurotoxin DSP-4 (N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine; 50 mg/kg i.p.) in the presence of the serotonin uptake inhibitor fluoxetine, 14 days prior to bilateral intracerebroventricular injection of AF64A (2 nmol/lateral ventricle). In rats in which noradrenaline (NA) was depleted by 94%, the loss of acetylcholine (ACh) in hippocampus induced by AF64A was significantly attenuated (p less than 0.02). However, when there was only a partial depletion of NA (50% reduction), the AF64A-induced loss of ACh was a pronounced as in rats with intact noradrenergic function. These findings indicate that the noradrenergic lesion has to be complete before a protective effect is apparent. Moreover, they imply that noradrenergic input is involved in AF64A-induced cholinergic damage in the hippocampus.

Adrenergic Fibers↗
PubMed1989

RBC and plasma choline in neuroleptic-treated schizophrenic patients.

We measured red blood cell (RBC) choline and plasma choline concentrations in 27 chronic schizophrenic inpatients and 23 normal controls. Both blood choline measures had a significant test-retest reliability in patients whose neuroleptic status remained unchanged over 1 month. RBC choline concentration was significantly lower in patients medicated with neuroleptics and cogentin. Patients with a low RBC choline and a low RBC/plasma choline ratio were on significantly higher doses of medication and had higher scores on the hostility/suspiciousness subscale of the Brief Psychiatric Rating Scale. RBC choline increased when neuroleptics were discontinued. Blood choline measures were also compared among medication-free schizophrenic patients, inpatients with other diagnoses, and normal controls. No significant differences were seen among these groups for any choline measure, although the schizophrenic patients showed greater variability. Medication-free schizophrenic patients with such clinical factors as tardive dyskinesia and abnormalities on computed tomography contributed to this variability. Age was positively correlated with plasma choline.

Adult↗
PubMed1989

Clonidine prevents transient loss of noradrenaline in response to cholinergic hypofunction induced by ethylcholine aziridinium (AF64A).

Intracerebroventricular injection of ethylcholine aziridinium (AF64A) (2 nmol/ventricle) induced a considerable decrease in the level of acetylcholine (ACh) in hippocampus (from 21.14 +/- 0.84 to 10.04 +/- 0.59 pmol/mg of tissue; p less than 0.001) 4 days after application. The reduction of cholinergic function was accompanied by a decrease in the level of noradrenaline (NA) (from 1.96 +/- 0.08 to 1.41 +/- 0.06 pmol/mg of tissue; p less than 0.001). Two days after administration of AF64A (1 or 2 nmol/ventricle), the dose-dependent decrease in NA level was associated with an increase in the level of its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), resulting in a considerable increase in the MHPG/NA molar ratio (from 0.84 +/- 0.06 to 1.62 +/- 0.17; p less than 0.002). Chronic treatment of AF64A-injected rats with clonidine (0.02-0.2 mg/kg, i.p., every 8-12 h) had no significant effect on the loss of ACh content, whereas the decrease in NA content in hippocampus was completely prevented. Clonidine induced aggressive behavior in the AF64A-treated rats, in contrast to sedation in vehicle-injected rats. The response to clonidine under these experimental conditions and the increased MHPG/NA molar ratio in response to AF64A suggest that the transient loss of NA content following AF64A administration results from increased NA release. The increased noradrenergic activity in hippocampus may be linked to the reduction of tonic inhibitory cholinergic input. These results are discussed in relation to possible implications for senile dementia of the Alzheimer type.

Acetylcholine↗