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Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of nerve growth factor in ethylcholine mustard aziridinium (AF64A)-treated rats: sensitization of cholinergic enzyme activity in the septohippocampal pathway.

In this study, we examined the effects of nerve growth factor (NGF) administration on cholinergic enzyme activity in both normal and ethylcholine mustard aziridinium (AF64A)-treated rats. Choline acetyltransferase (ChAT) and acetylcholinesterase activity were measured in the hippocampus and septum of rats chronically administered NGF (0.36-2.85 micrograms/day) into the lateral ventricle for 14 days. In both normal and AF64A-treated rats, NGF increased cholinergic enzyme activity in a dose-dependent manner. Furthermore, although NGF increased ChAT activity in normal rats by 147%, it had a greater effect in AF64A-treated rats, increasing ChAT activity as much as 273%. NGF increased acetylcholinesterase activity in normal rats by only 125% but produced a 221% increase in this activity in AF64A-treated rats. These data indicate that AF64A produces an increased sensitivity to NGF in cholinergic neurons.

Animals↗
PubMed1994

Long-term exposure to high levels of corticosterone aggravates AF64A-induced cholinergic hypofunction in rat hippocampus in vivo.

Male Sprague-Dawley rats were bilaterally adrenalectomized and corticosterone (CORT) was substituted as subcutaneous pellets in two groups of animals: low- (L-CORT: 1 x 25 mg pellet) or high-level of CORT (H-CORT: 4 x 100 mg pellet). Between 14 and 19 days after CORT substitution, ethylcholine aziridinium (AF64A) was intracerebroventricularly (i.c.v.) injected in the CORT long-term exposed rats and the dose- and time-dependent effect of this treatment was measured on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in hippocampus and septum and on serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and noradrenaline (NA) levels in hippocampus. Rats were killed at 2, 4, 7 and 14 days after AF64A treatment. Starting 4 days after the i.c.v. administration of 0.5 or 1.0 nmol of AF64A, an aggravation of the reduction of ChAT activity was measured in the hippocampus of the H-CORT animals compared to the L-CORT ones. In the septum of the H-CORT rats, the activity of ChAT increased within the first week after the infusion of the toxin, while no significant effect was observed in the L-CORT group. As we observed with ChAT, AF64A induced a severe inhibition of AChE activity in the hippocampus of the H-CORT rats compared to the L-CORT ones. In the septum, an increase of AChE activity was observed in both groups of CORT-exposed animals. In the hippocampus of H-CORT animals, the exacerbation of the inhibition of ChAT and AChE activity was accompanied by a parallel decrease in the content of 5-HT and 5-HIAA starting 4 days after AF64A injections. Finally, NA content in hippocampus was not affected by the toxin in the CORT-substituted animals. These data demonstrate that: (1) long-term exposure to supraphysiological levels of CORT enhances the cholinodisruption induced in hippocampus by AF64A, at doses of 0.5 and 1.0 nmol/side; (2) high circulating plasma CORT concentrations impair hippocampal cholinergic neuronal capacity to recover from damage; and (3) the degree of inhibition of the serotoninergic system is augmented in H-CORT animals, most probably due to an adaptation of the serotoninergic neurons to the larger withdrawal of cholinergic function observed in this group.

Acetylcholinesterase↗
PubMed1994

Cholinotoxic effects on acetylcholinesterase gene expression are associated with brain-region specific alterations in G,C-rich transcripts.

To study the mechanisms underlying cholinotoxic brain damage, we examined ethylcholine aziridinium (AF64A) effects on cholinesterase genes. In vitro, AF64A hardly affected cholinesterase activities yet inhibited transcription of the G,C-rich AChE DNA encoding acetylcholinesterase (AChE) more than the A,T-rich butyrylcholinesterase (BChE) DNA. In vivo, intracerebroventricular injection of 2 nmol of AF64A decreased AChE mRNA in striatum and septum by 3- and 25-fold by day 7, with no change in BChE mRNA or AChE activity. In contrast, hippocampal AChE mRNA increased 10-fold by day 7 and BChE mRNA and AChE activity decreased 2-fold. By day 60 post-treatment, both AChE mRNA and AChE levels returned to normal in all regions except hippocampus, where AChE activity and BChE mRNA were decreased by 2-fold. Moreover, differential PCR displays revealed persistent induction, specific to the hippocampus of treated rats, of several unidentified G,C-rich transcripts, suggesting particular responsiveness of hippocampal G,C-rich genes to cholinotoxicity.

Acetylcholinesterase↗
PubMed1994

The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine.

The study describes a sequential analysis of depression-related physical symptoms and their relationship to imipramine and amitriptyline plasma levels over 4 weeks of treatment in 79 unipolar and bipolar patients hospitalized for major depressive disorder. Insomnia diminished in all patients after 2 weeks of drug administration. After 4 weeks, the sleep of patients whose depressive disorder has significantly improved was nearly normal, whereas patients who remained depressed showed continued sleep impairment. Reductions in loss of appetite, weight and sexual interest paralleled mood improvement. Tricyclic plasma levels significantly correlated with improved sleep. The findings suggest a close link between depressed mood and physical symptoms during recovery from major depressive disorder.

Adult↗
PubMed1994

AF64A affects septal choline acetyltransferase but not parvalbumin immunoreactive cells.

Rats received bilateral intracerebroventricular (ICV) infusions of either AF64A (1.5 nmol/ventricle; n = 9) or vehicle (3.0 microliters/ventricle; n = 7). Four weeks later, the animals were anesthetized and their brains processed to visualize and quantify choline acetyltransferase (ChAT) immunoreactive (IR) and parvalbumin-IR GABAergic neurons in the septal complex by immunocytochemistry (PAP method). AF64A significantly reduced the number of ChAT-IR perikarya in the medial septum (28%), ventral limb of the diagonal band of Broca (30%), and horizontal limb of the diagonal band of Broca (20%), but did not affect the number of parvalbumin-containing GABAergic neurons in any of the septal subdivisions. These results provide further evidence that AF64A is a selective cholinotoxin.

Animals↗
PubMed1994

Comparison of the effects of natural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo.

(-)-Huperzine-A has been shown to be a promising agent for the treatment of dementia of the Alzheimer type. This substance is rare in nature. We have been able to prepare a racemic mixture of (+/-)-huperzine-A in quantity. In the absence of a chiral synthetic procedure for (-)-huperzine-A, this study sought to determine whether the racemic mixture would yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixture (+/-)-huperzine-A was 3 times less potent than (-)-huperzine-A in vitro (IC50s of 3 x 10(-7) M and 10(-7) M, respectively) because the former consisted of a racemic mixture of the compound in which the (+)-huperzine component was considerably less potent (IC50 = 7 x 10(-6) M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1-2.0 mg/kg administered intraperitoneally (i.p.), both (-)-huperzine-A and (+/-)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus and frontal cortex). This inhibition of acetylcholinesterase activity was inversely related to levels of acetylcholine measured in the hippocampus and followed the same time course of effect. (-)-Huperzine-A and (+/-)-huperzine-A were shown to be more potent than physostigmine as inhibitors of acetylcholinesterase in vitro (IC50 = 6 x 10(-7) M).

Acetylcholinesterase↗
PubMed1993

Natural and synthetic Huperzine A: effect on cholinergic function in vitro and in vivo.

Huperzine A has been shown to be useful in the treatment of symptoms of dementia of the Alzheimer type. Our initial attempts to synthesize (-)Huperzine A resulted in the racemic mixture of (+/-)Huperzine A. We have therefore compared the in vitro and in vivo effects of (+/-)Huperzine A with those of (-)Huperzine A in rats. The results indicate a similar biological mechanism of action between the two, but that the racemic mixture of (+/-)Huperzine A has a weaker biological activity than the natural product (-)Huperzine A, presumably due to the presence in the mixture of (+)Huperzine A, which is considerably less potent than the (-)isomer.

Acetylcholine↗
PubMed1993

UCB 29120, a novel, potential psychotropic agent, alters norepinephrine and dopamine content of rat brain.

UCB 29120 belongs to a novel family of compounds possessing interesting behavioral and physiological properties. Behavioral studies in the rat have revealed the ability of the compound to inhibit scopolamine-induced amnesia while physiological studies demonstrated a significant drug-induced hypothermic response and increase corticosterone plasma levels following acute administration of the compound. In the present study we examined the time-course effects of acute administration of UCB 29120 on levels of catecholamines (norepinephrine, NE; dopamine, DA), indoleamines (serotonin, 5-HT) and metabolites (3,4-dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5-HIAA) in the rat hypothalamus. Hippocampal, septal and striatal tissue content of the same were also examined at the longest time point employed. In the hypothalamus, UCB 29120 induced significant decreases in NE content 30 min following administration which persisted for at least an additional 30 min, while significant increases in DA and/or DOPAC (and the DOPAC/DA ratio) were measured as early as 5 min following administration and persisted through at least a total of 120 min. Similar, significant changes in dopaminergic parameters were also evident in the other three brain regions at 120 min post-administration. No significant alterations in hypothalamic 5-HT or 5-HIAA were measured at any time point. Acute administration of UCB 29120 may selectively influence catecholaminergic neurotransmitter systems in rat brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Sex differences and estrous cycle-variations in the AF64A-induced cholinergic deficit in the rat hippocampus.

The influence of gender and stage of the estrous cycle on the levels of acetylcholine, serotonin, and noradrenaline in the hippocampus and on the susceptibility of the cholinergic septo-hippocampal pathway to the neurotoxic effect of ethylcholine aziridinium (AF64A) was investigated in the rat. Levels of acetylcholine and serotonin were consistently higher in female rats during the stage of diestrus and proestrus than in age-matched male rats (p < 0.05). Across the estrous cycle the highest levels of acetylcholine and serotonin, coinciding with the lowest levels of noradrenaline, were measured on proestrus. Eight to 10 days after the bilateral intracerebroventricular injection of a submaximal dose of AF64A (1 nmol/ventricle) the decrease of acetylcholine in hippocampus was larger in females than in male rats. The reduction of acetylcholine was most pronounced in female rats that had received submaximal doses of AF64A on proestrus (42.7 +/- 3.4%), whereas in male rats, the corresponding decrease was 25.9 +/- 5.1% (p < 0.05). At a maximal dose of AF64A (2 nmole/ventricle), the sex-specific or cycle-dependent difference in the cholinotoxicity of AF64A vanished. The dose-dependent loss of acetylcholine was associated with a secondary dose-dependent decrease in the levels of serotonin and noradrenaline, but significant differences between male and female rats or stages of estrous cycle were not apparent. The present data provide evidence that adult female rats in general, and particularly females on proestrus, are more susceptible to the neurotoxic action of submaximal doses of AF64A than age-matched male rats.

Animals↗
PubMed1993

ucb 11056, a new potential nootropic drug, amplifies induced cyclic AMP formation in rat brain tissue.

ucb 11056 [2-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)aminoethanol] induced a significant (approximately 25%) increase in cyclic AMP levels in different brain areas following its intraperitoneal injection. This effect started as early as 2 min postinjection and lasted for 30 min, after which cyclic AMP levels returned to normal. In hippocampal slice preparations in vitro, ucb 11056 exerted a strong potentiation of cyclic AMP levels when it was combined with agents such as norepinephrine, forskolin, and isoproterenol. Only a slight effect on cyclic AMP levels was measured when ucb 11056 was incubated alone with hippocampal slices. The potentiating effect of ucb 11056 on norepinephrine-stimulated cyclic AMP formation was partially reduced when slices were pretreated with yohimbine and totally abolished when slices were treated with propranolol. These combined data indicate that (a) ucb 11056 rapidly increases cyclic AMP levels in the rat brain in vivo and (b) ucb 11056 potentiates stimulated cyclic AMP formation in vitro. The data also suggest that the central effect of ucb 11056 might be via the modulation of cyclic AMP generation, most probably mediated through adenylate cyclase activation mechanisms combined with a weak inhibitory activity on the cyclic nucleotide phosphodiesterase activity.

Analysis of Variance↗
PubMed1992

Behavioural, biochemical and histological effects of AF64A following injection into the third ventricle of the mouse.

Behavioural, biochemical and histological effects were assessed following AF64A injected into the third ventricle of female NMRI mice. Doses from 3 to 7 nmol produced significant changes in behaviour, causing hyperactivity, reduced hole-board exploration, rotational behaviour in a symmetrical Y-maze corresponding to a loss of alternation, abnormal behaviour in a plus-maze task of fear/anxiety with markedly increased exploration of the open arms and finally deficits in passive avoidance responding and spatial orientation in a Morris-type water maze. In this latter test, a cue learning deficit was noted for the two highest doses only. No histological changes of consequence were observed up to 5 nmol. Beyond this dose, at 6 and particularly 7 nmol, necrosis of parts of the hippocampus and septum was apparent. ChAT and AChE activity were decreased in the hippocampus but not in the cortex although the decreases were smaller than generally reported for AF64A-treated rats. ChAT and AChE reductions correlated highly with hyperactivity in the open-field and to a lesser extent, with spatial learning deficits. Monoaminergic activity was also affected in the hippocampus, but not in the cortex, at 4 nmol and above. NE and particularly 5-HT and 5-HIAA levels were reduced although the rate of 5-HT turnover was unaltered. A highly significant correlation was obtained between 5-HT effects and the increased open arm exploration in the plus-maze task of fear/anxiety. The behavioural effects and biochemical changes lasted at least 8-9 weeks postop.

Acetylcholinesterase↗
PubMed1992

Controlled study of erythrocyte choline in Tourette syndrome.

Erythrocyte and plasma choline parameters were compared in children (n = 63), aged 6-18 years, suffering from Tourette Syndrome (TS), their parents (n = 57), their unaffected siblings (n = 38), and an adult control group (n = 57). Factors such as severity of illness, medication status, and gender had no effect on erythrocyte choline. TS patients showed elevations in erythrocyte choline level compared to controls. Furthermore, the erythrocyte choline concentration in TS patients with a history of TS or chronic motor tic disorder (CMT) in first-degree relatives showed a positive correlation with that of their parents (r2 = 0.6, p less than 0.03). Erythrocyte choline values in TS patients without such positive family history do not demonstrate a familial relationship. Positive history of TS or CMT in first-degree relatives accounts for the observation of elevated erythrocyte choline in unaffected siblings of TS patients. Age effects on erythrocyte choline were found in the TS patients only (r = -0.14, p less than 0.04) and not in parents, siblings, or normal controls. A gender effect on plasma choline was noted with male levels 23% higher than in females. The present findings support the utility of erythrocyte choline as a marker for the familial expression of the TS diathesis.

Adolescent↗
PubMed1992

Reversible cholinergic changes induced by AF64A in rat hippocampus and possible septal compensatory effect.

Ethylcholine aziridinium (AF64A) was injected intracerebroventricularly in rats, and the dose- and time-dependent effect of this treatment was measured on cholinergic markers in different areas of the brain. Choline acetyltransferase (ChAT) in the hippocampus was reduced by 0, 25, 40 and 50%, 4 days after administration of 0.25, 0.5, 1.0 and 2.0 nmol/side of AF64A. This effect was paralleled by a 0, 21, 38 and 48% increase in septal ChAT, at the same time and dose, respectively. Hippocampal and septal ChAT returned to normal by 14 days, following the two smaller doses of AF64A. Normal values of ChAT activity in the hippocampus were measured by 3 months post-1.0 nmol/side and by 12 months after 2.0 nmol AF64A/side. A transient secondary increase in septal ChAT was measured at 28 and 42 days after 1.0 nmol/side, after which no further changes were measured in this area. High affinity choline transport (HAChT) in the hippocampus showed a 35 and 25% decrease but only 14 and 7 days, after injection of 0.25 and 0.5 nmol AF64A/side, respectively. However, significant reductions by 45% at 14 days and by 65% at 4 days, were measured after the infusion of 1.0 and 2.0 nmol/side, respectively. This effect was significantly attenuated by 3 months and returned to normal by 12 months after treatment. Acetylcholinesterase (AChE) activity in the hippocampus was most severely affected by AF64A. Specifically, significant inhibition of 20% (by 7 days), 35% (by 7 days), 25% (by 2 days) and 30% (by 2 days) was observed at 0.25, 0.5, 1.0 and 2.0 nmol AF64A/side, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Development of a sensitive and inexpensive micropush-pull technique for the continuous analysis of brain neurotransmitters and metabolites in vivo.

A new, sensitive, convenient, inexpensive and low-maintenance miniaturized triple-cannula system (Zhange et al., 1990) for the push-pull perfusion of brain tissue has been constructed, and tested for its ability to exchange substances in rats, both in vitro and in vivo. In vitro: the cannula was immersed in a vial filled with 1.5 ml of a 1 microM standard solution of norepinephrine, dopamine, and their metabolites. Artificial cerebrospinal fluid was perfused through the system. Perfusate was collected at rates of 1, 2, 5, 10 and 20 microliters/min over 10 min. The recovery rate of the biogenic amines (using high performance liquid chromatography) at 10-min intervals for 60 min was consistent (57 +/- 1.31%) in low flow rate groups (1 approximately 10 microliters/ml). In vivo: [3H]choline (3 microCi, 35 nmol) was infused (6 min) into the lateral ventricle and collected by micropush-pull at 10-min intervals for 180 min, from the cerebellomedullary cistern and hippocampus. The highest [3H]choline count was reached within 10 min after infusion. Levels returned to baseline within 20 min following infusion of the tracer. The micropush-pull cannula was also adapted for chronic brain perfusion in vivo. Recovery of perfused fast green dye (0.00025%) was comparable (83 +/- 1.75%), using the same cannula for 3 sampling periods within 1 month in a freely moving rat. A cresyl violet analysis showed minimal damage to the brain tissue, with gliosis only evident in a narrow margin along the cannula track. Thus the micropush-pull technique is highly efficient in terms of exchange of material, causes minimal damage of brain tissue, and can be used chronically in awake animals. These data have been presented in preliminary form at the 1991 ASPET meetings (Zhang et al., 1991).

Anesthesia↗
PubMed1992

DNA-damaging and transcription-terminating lesions induced by AF64A in vitro.

Although immediate cholinergic deficits produced by AF64A can be explained adequately by inhibition of enzymes involved in acetylcholine metabolism, the structural similarity of AF64A to a number of DNA-damaging antitumor agents suggested that the observed long-term cholinergic deficits may involve damage to the cell's informational molecules. This study was initiated to determine if AF64A can damage DNA and prematurely terminate RNA transcription in vitro, and to produce cytotoxic and DNA damaging effects in cells exposed to the drug in vivo. The ability of AF64A to produce N-7 guanine alkylations in DNA in vitro was assessed using a modified Maxam and Gilbert DNA sequencing technique, and the ability of AF64A to terminate RNA transcription was assessed by an in vitro RNA transcription system. AF64A was capable of producing extensive dose-dependent N-7 guanine alkylations in DNA fragments exposed to AF64A in vitro, although no sequence specificity of AF64A attack could be discerned. Furthermore, AF64A was able to produce RNA transcription-terminating lesions in vitro, also in a dose-dependent fashion. Transcription of AF64A-damaged DNA resulted in RNA molecules terminated not at every alkylated guanine, but at various discrete sites along the DNA template. AF64A was also found to be cytotoxic in a dose-dependent manner in cultured mouse leukemia L1210 cells. The induced cytotoxicity was accompanied by DNA lesions which were detected as DNA single strand breaks using the DNA alkaline elution technique. The results of these experiments support the hypothesis that AF64A may alter the structure and function of cellular DNA and may help explain the observed long-term cholinergic deficits.

Animals↗
PubMed1991

Erythrocyte choline concentration in bipolar disorder: a predictor of clinical course and medication response.

Erythrocyte choline concentrations were measured in hospitalized patients with bipolar disorder, manic phase, and control subjects. There was a significant elevation in mean erythrocyte choline in the patients with mania. This elevation in erythrocyte choline was due to a subgroup of patients with especially high values. Significant clinical differences were apparent between the patients with "high" and those with "low" erythrocyte choline concentrations. The subgroup of manic patients with elevated erythrocyte choline had a more severe illness at admission, a worse outcome at discharge, and required significantly more neuroleptic during hospitalization than their low choline counterparts; that is, they were less likely to respond well to lithium alone. Furthermore, the bipolar patients with low erythrocyte choline concentrations, as a whole, had more than four times as many previous manic episodes than depressive episodes, while the patients with high choline values had approximately the same number of past manias and depressions. These results are discussed in light of the evidence implicating cholinergic neurotransmission in the pathophysiology of affective disorders. In addition, the design of future clinical studies of erythrocyte choline and its possible clinical utility are discussed.

Adolescent↗