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Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 19 recordsLinked to original sources
PubMed2005

Low intracerebroventricular doses of cholinotoxin AF64A do not affect the morphology of gonadotropin hormone-releasing hormone (GnRH)-immunoreactive fibers in the rat septum.

Ethylcholine aziridinium (AF64A) induces cholinergic lesion in animal models of AD. Although higher concentrations of AF64A are known to induce nonspecific, cholinergic, and non-cholinergic lesions, low concentrations are believed to be selectively cholinotoxic. However, morphological evidence of this phenomenon has not been demonstrated yet. The present study demonstrates that while AF64A damaged septal cholinergic fibers, periventricular GnRH-immunoreactive fibers remained intact, confirming the highly selective cholinotoxicity of AF64A at appropriate concentrations.

Animals↗
PubMed2004

Glycosaminoglycan C3 protects against AF64A-induced cholinotoxicity in a dose-dependent and time-dependent manner.

Several studies revealed that proteoglycans (PGs) and glycosaminoglycans (GAGs) play a pivotal role in the pathogenesis of Alzheimer's disease (AD). PGs have affinity to amyloid beta (Abeta) and protect it against proteolysis, and the consequent aggregation is the cause of neurotoxicity. This effect is believed to be attenuated by GAGs. Moreover, a low-molecular-weight GAG C3 derived from unfractionated heparin has been reported to protect against Abeta-induced tau-2 immunoreactivity and cholinergic damage induced by a cholinotoxin, AF64A, in rat. However, the optimal dose and the timeframe of administration of C3 are still unknown. In our studies, we revealed the concentration-dependent and time-dependent effects of C3 on AF64A-induced cholinergic lesion in rat. C3 was administered orally in 5, 10, and 25 mg/kg/day concentration, 7 days before and/or 7 days after intracerebroventricular (i.c.v.) AF64A administration. Our results have shown that 25 mg/kg/day C3 effectively protects against AF64A-generated cholinotoxicity if administered both 7 days before and 7 days after the AF64A injection. In contrast to these findings, administration of 5 or 10 mg/kg/day C3 or 25 mg/kg/day C3, given 7 days before or 7 days after stereotaxic AF64A injection, did not show cholinoprotective effects. In conclusion, the time-dependent effects of C3 on AF64A-induced cholinergic lesion suggest that C3 may act via the processes of both neuroprotection and neurorepair. Moreover, the effects of C3 depend largely on the administered dose of this low-molecular-weight GAG. The present findings also indicate that C3, administered in the effective concentration and timeframe, may play a pivotal role in the treatment of AD.

Acetylcholinesterase↗
PubMed2000

A ventral approach to stereotaxy of the guinea pig brain.

The guinea pig (Cavia porcellus) is a species frequently used in neuromorphological and neurophysiological studies. Some experimental data suggest that the guinea pig might also be used to develop an animal model of Alzheimer's disease. These studies would require microsurgical manipulations of the nervous system. The present paper describes a method for ventral stereotaxic intrusions in the guinea pig brain through the oval foramen at the skull base. The topographic relationships of the bony landmarks to major parts of the central nervous system and the cranial nerves are analysed, and the results are tested by intrahippocampal injection of horseradish peroxidase.

Animals↗
PubMed1999

Effects of AF64A on gene expression of choline acetyltransferase (ChAT) in the septo-hippocampal pathway and striatum in vivo.

AF64A (ethylcholine mustard aziridinium ion) was stereotaxically administered bilaterally (1 nmol/side) into rat lateral cerebral ventricles. Choline acetyltransferase (ChAT) activity and ChAT mRNA levels were measured at predetermined time points in the septo-hippocampal pathway and striatum, both well identified as rich in cholinergic neurons. AF64A caused a rapid but transient increase in ChAT mRNA (167%, P < 0.05) and ChAT activity (164%, P < 0.01) in the septum. By day 7 post treatment, there was a significant decrease in ChAT mRNA (42.5% of control, P < 0.05) in the septum although the ChAT activity still stayed high. This decreased ChAT mRNA level in the septum lasted for at least four weeks, and was paralleled by a long-lasting decrease in ChAT activity in the hippocampus. In the striatum, on the other hand, there were no observed changes in either ChAT activity or ChAT mRNA. These data suggest that the long term effect of AF64A on the septo-hippocampal cholinergic pathway may, at least in part, be due to an action of AF64A on gene expression in the cholinergic neuron. The difference in the response to AF64A between the septo-hippocampal and striatal cholinergic systems might be due to their difference in neuron types.

Animals↗
PubMed1998

Cerebrospinal fluid free choline in movement disorders of paediatric onset.

We measured free choline in cerebrospinal fluid (CSF) of 78 patients with movement disorders of paediatric onset and various controls as a putative index of central phospholipid metabolism. Most of the disorders studied were myoclonic disorders, such as progressive myoclonus epilepsy, the opsoclonus-myoclonus syndrome, and essential myoclonus, but other movement disorders, interictal seizure disorders, and different neurological and nonneurological disorders were also included. There were no significant differences in CSF choline concentrations in myoclonic disorders or other movement disorders compared with controls. The CSF choline levels were lowest in children with seizure disorders including progressive myoclonus epilepsy. In progressive myoclonus epilepsy, the CSF choline values resembled other epileptic disorders rather than other myoclonic disorders. When all the data were analysed collectively, no significant relation of CSF choline was found to patient age, gender, aliquot of CSF measured, or the length of time the sample was stored at -70 degrees C. Separate analyses of data from children and adults showed a trend toward a biphasic relation between patient age and CSF choline which could be pursued in developmental studies of normal subjects. Reduced CSF choline may indicate increased choline incorporation into brain phospholipids, disturbances of choline metabolism, decreased choline release, or non-neural factors.

Acetylcholine↗
PubMed1998

AF64A-induced changes in N-myc expression in the LA-N-2 human neuroblastoma cell line are modulated by choline and hemicholinium-3.

Due to AF64A's structural similarity to choline, AF64A can selectively affect cholinergic neurons, which possess a high affinity choline transport system for acetylcholine synthesis. The mechanism by which AF64A selectively produces its cytotoxic effect is unknown. However, based on previous studies that demonstrate that DNA lesions produced by AF64A caused premature termination of N-myc transcription in vitro, it is possible that AF64A may affect the transcription of genes necessary for developmental maintenance in cholinergic cells. Using the LA-N-2 cells as a model to study the effects of AF64A in a purely cholinergic system, we investigated the effects of AF64A on the expression of the N-myc gene and monitored cell growth. AF64A produced a maximal decrease in N-myc mRNA with a return to steady state levels at later time points. Moreover, a decrease in cell numbers in AF64A-treated cells was observed, and these cells did not double in number at their respective doubling time as compared to control. In other studies, a causal relationship between a reduction in N-myc and an inhibition of cell growth and replication has been reported. While these studies do not allow us to conclude that AF64A is specific for N-myc, the data do, nevertheless, suggest that AF64A affects cell growth and/or replication by down-regulating the expression of N-myc which is involved in differentiation and cell growth in neuroblastomas. Presence of choline or hemicholinium-3 prevented the AF64A-induced decrease of N-myc levels by competing with, or inhibiting the choline transport mechanism by which AF64A enters the cell, respectively.

Aziridines↗
PubMed1998

Mivazerol inhibits intrathecal release of glutamate evoked by halothane withdrawal in rats.

BACKGROUND: Mivazerol is a new and selective alpha 2-adrenergic receptor agonist devoid of hypotensive effects (1, 2). Previous studies have demonstrated that mivazerol prevents hemodynamic instability during emergence from halothane anesthesia in rats (3). The present study was to determine whether glutamate and aspartate are involved in this action of mivazerol, at the second to third thoracic segments (T2-T3) of the spinal cord. METHODS: In vivo microdialysis in combination with high-performance liquid chromatography (HPLC) was employed in the study. Blood pressure (BP) and heart rate (HR) were recorded along with intrathecal (i.t.) microdialysis perfusion. RESULTS: BP, HR and i.t. release of glutamate (GLU, pmol/microliter) were stable in the rats under 1.1% halothane anesthesia. However, halothane withdrawal immediately increased BP, HR, and i.t. release of GLU, and remained elevated for at least 2 h after withdrawal of halothane. Thirty minutes prior to halothane withdrawal, intravenous (i.v.) infusion of mivazerol (15 micrograms.kg-1.h-1) almost completely prevented the increases in HR (delta 18 +/- 7 vs delta 79 +/- 7 beats/min), and in the i.t. release of GLU (delta 10.3 +/- 3.7 vs delta 30.6 +/- 5.9; 112% vs 167%). Local i.t. microinjection of mivazerol (2.5 micrograms/kg) 2 min prior to withdrawal of halothane also blocked the HR responses, as well as on the i.t. release of GLU following halothane withdrawal. CONCLUSION: The present study demonstrates that emergence from halothane anesthesia increases i.t. release of GLU, and that mivazerol has an inhibitory effect on the above, through its direct action on the spinal cord.

Adrenergic alpha-Agonists↗
PubMed1997

Brain-derived neurotrophic factor induced stimulation of septal choline acetyltransferase activity in ethylcholine mustard aziridinium treated rats.

We evaluated whether brain-derived neurotrophic factor (BDNF) can stimulate choline acetyltransferase (ChAT) activity in the septo-hippocampal pathway of ethylcholine mustard aziridinium (AF64A) and non-AF64A-treated rats. Rats received either AF64A (1.5 nmol/ ventricle) or a sham (non-AF64A-treated) injection into the lateral ventricles. BDNF infusion (at a dose range of 0.1-171 microg) into either the lateral ventricle or hippocampus of AF64A-treated rats for 14 days increased septal ChAT activity (26% and 41%, respectively). BDNF did not reverse the decrease in hippocampal ChAT activity (20-60%) produced by AF64A. BDNF infusion did not change ChAT activity in the septo-hippocampal pathway of non-AF64A-treated rats. Thus, septo-hippocampal cholinergic neurons in AF64A-treated rats are sensitive to BDNF while those of non-AF64A-treated rats (normal) are not responsive to this neurotrophin.

Animals↗
PubMed1997

Bradycardia induced by mivazerol, a selective alpha 2-adrenoceptor agonist, is amplified during mild hypothermia in the pentobarbital-anesthetized rat.

Mivazerol, 3-[1(H-imidazol-4-yl)methyl]-2-hydroxybenzamide hydrochloride, is a selective alpha 2-adrenoceptor agonist designed for the prevention of myocardial infarction in perioperative patients. Because unintended hypothermia occurs frequently during surgery, we were interested, in this study, to examine the relationship between body temperature and the bradycardic response induced by mivazerol. Experiments were carried out in pentobarbital-anesthetized and artificially ventilated rats. The femoral artery and vein were cannulated for the measurement of blood pressure and heart rate, and for intravenous infusion. Rectal temperature was maintained at 37.5 +/- 0.3 degrees C for normothermic groups or at 35.5 +/- 0.3 degrees C for hypothermic groups. Intravenous infusion of vehicle had no significant effect on mean arterial pressure and heart rate between the normothermic and hypothermic rats. Mivazerol dose-dependently produced a decrease in heart rate in normothermic rats, which became more pronounced in mildly hypothermic rats, but did not induce any significant change in mean arterial pressure in either thermic condition. These results show that the bradycardic effect of mivazerol, an alpha 2-adrenoceptor agonist, is amplified during mild hypothermia, a condition that occurs frequently in perioperative patients.

Adjuvants, Anesthesia↗
PubMed1997

Mivazerol, a new alpha 2-adrenergic agonist, blunts cardiovascular effects following surgical stress in pentobarbital-anesthetized rats.

BACKGROUND: Mivazerol is a new and selective alpha 2-adrenoceptor agonist, devoid of hypotensive effects, which has been designed to prevent adverse cardiac outcome in perioperative patients with, or at risk coronary artery disease. METHODS: In the present study, the effects of mivazerol on hemodynamic changes induced by trachea-exposure surgery stress were investigated in pentobarbital-anesthetized rats, and compared to those of dexmedetomidine. RESULTS: Intravenous infusion of 3 different doses of mivazerol (3.75, 7.5 and 15 micrograms.kg-1.h-1) did not significantly alter BP but caused a dose-related decrease in HR. The maximal decrease in HR was approximately 87 beats/min. Contrary to mivazerol, dexmedetomidine (7.5 micrograms.kg-1.h-1, i.v.) decreased both BP (11 +/- 3.2 mmHg) and HR. The maximum decrease in HR was approximately 104 beats/min. Surgical stress produced a rapid increase in BP (maximal increase of 50 mmHg) and HR (maximal increase of 100 beats/min), which lasted for at least 15 min. Constant infusion of mivazerol, at dose of 15 micrograms.kg-1.h-1, beginning 20 min prior to surgery and lasting for 35 min, significantly inhibited surgical stress-induced increases in BP (P < 0.05) and HR (P < 0.001). Dexmedetomidine, at a dose which produced hypotension and profound bradycardia prior to surgery, did not have any effect on the surgical stress-induced elevation in BP (P > 0.05), but prevented the increase in HR (P < 0.05). Pretreatment with the alpha 2-adrenoceptor antagonist rauwolscine (0.5 mg/kg, i.v.) blocked the bradycardia induced by mivazerol as well as the inhibitory effect of mivazerol on surgical stress-induced elevations in HR and BP. CONCLUSION: Mivazerol attenuates surgical stress-induced elevations in BP and HR during pentobarbital anesthesia in rats, and these effects are mediated by stimulation of alpha 2-adrenoceptors. Unlike dexmedetomidine, mivazerol does not reduce BP, and is also more potent than dexmedetomidine in blunting surgical stress-induced increases in BP in pentobarbital-anesthetized rats.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

Mivazerol, a selective alpha 2-adrenoceptor agonist, attenuates tachycardia by intrathecal injection of N-methyl-D-aspartate in the rat.

The intravenous (i.v.) infusion of mivazerol, a new selective alpha 2-adrenoceptor agonist, produced a significant decrease in heart rate but not in blood pressure in pentobarbital-anesthetized Sprague-Dawley rats. The tachycardic response to intrathecal (i.t.) injection of N-methyl-D-aspartic acid (NMDA) was significantly attenuated by the i.v. infusion of mivazerol. The i.t. pretreatment with yohimbine significantly attenuated the bradycardic response to i.v. mivazerol and blocked the effect of mivazerol on the tachycardic response to i.t. NMDA. These results suggest that (1) the bradycardic effect of mivazerol is mediated, at least partly, by spinal alpha 2-adrenoceptors; and (2) there is a possibility of functional antagonism between spinal alpha 2-adrenoceptors and NMDA receptors in the regulation of heart rate.

Adrenergic alpha-Agonists↗
PubMed1996

Age-dependent effect of AF64A on cholinergic activity in the septo-hippocampal pathway of the rat brain: decreased responsiveness in aged rats.

Our previous studies have demonstrated that intracerebroventricular (icv) administration of low doses of ethylcholine mustard aziridinium (AF64A), up to 1.0 nmol/side, induces a reversible cholinergic deficit in the hippocampus, paralleled by a compensatory transient increase in choline acetyltransferase (ChAT) activity in the septum [El Tamer, A., Corey, J., Wülfert, E. and Hanin, I., Neuropharmacology, 31 (1992) 397-402]. In the present study we have addressed the question as to whether this effect might differ in old rats. AF64A (0.5 nmol/side) icv administered to three groups of rats aged 4, 12 and 22 months, respectively, induced a reduction of ChAT activity in the hippocampus to the same extent (-26%, -30.6% and -29.6%; P < 0.01) by 7 days post-icv injection. Acetylcholinesterase (AChE) was decreased to a similar extent in the 4 and 12 month old rats (-22% and -29%; P < 0.01), respectively, but remained unchanged in the 22 month old group. Whereas AChE activity remained unchanged in the septum in all three groups of rats, ChAT activity was increased significantly (+20% and +20.8%; P < 0.05 versus corresponding control group) in the 4 and 12 month old groups, respectively. No change in ChAT activity was measured in the septum of the 22 months old group. By 14 days post-icv injection of AF64A, ChAT and AChE activities were back to normal in all three groups and in both brain regions studied. These results demonstrate that a difference in AF64A's effect does exist between the 22 month old group and the youngest group. This might reflect a possible age-dependent change in the ability of the cholinergic system to respond to the cholinotoxicity of AF64A, as well as in the potential of the cell bodies, at the septal level, to respond to such an insult by a compensatory mechanism such as increasing ChAT activity.

Acetylcholinesterase↗
PubMed1996

The AF64A model of cholinergic hypofunction: an update.

Based on numerous reports in the literature since 1980, one can now conclude that ethylcholine aziridinium (AF64A) is selective for the cholinergic system in vivo, and that the effect is both dose- and site-dependent. Thus, AF64A treatment, under the correct conditions of dose and time will result in selective reductions in levels of ACh, AChE, ChAT, HAChT, and K(+)- and ouabain-stimulated release of ACh. While other neurotransmitters may also be affected in brains of AF64A treated rats, the effect is only transient and is most probably secondary to the initial cholinergic deficit-induced by AF64A, reflecting an adaptive reaction of these neurotransmitter systems, which are normally integrated with cholinergic interconnections, to the cholinergic deficiency induced by AF64A. This paper provides a historical perspective for the development of AF64A as a selective cholinotoxin, and surveys its potential mechanisms of action at the neurochemical and molecular levels. Moreover, the availability of an animal model such as the AF64A-treated rat, in which the cholinergic system has been compromised selectively for an extended period of time, has allowed investigators to study a wide variety of questions that relate to factors controlling cholinergic function in vivo. Several key illustrations are presented at the end of this paper.

Animals↗
PubMed1996

Mivazerol, a novel alpha2-agonist and potential anti-ischemic drug, inhibits KC1-stimulated neurotransmitter release in rat nervous tissue preparations.

In this study, we have investigated the effect of mivazerol, [3-(1H-imidazol-4-yl)methyl-1]-2-hydroxy-benzamide hydrochloride, a new alpha2-agonist lacking hypotensive properties and a potential anti-ischemic drug, on the evoked release of norepinephrine, aspartate, and glutamate in tissue preparations from hippocampus, spinal cord T1-T5 section, rostrolateral ventricular medulla, and nucleus tractus solitarii of the brainstem of rat. A simple and efficient in vitro procedure to study pharmacologically the release of norepinephrine and glutamate is described. Tissues were chopped into (0.3 x 0.2 x 0.2 mm3) sections and the resulting minces were used for this study. Exposure to KCl (10-75 mM) for 5 min served as a stimulus for the release response. One, S (for aspartate and for glutamate release), or two such stimuli, S1 and S2 (for norepinephrine release) were conducted. The release of norepinephrine (+ 150% above baseline) was inhibited in a dose-dependent manner by mivazerol in hippocampus (IC50 = 1.5 x 10(-8) M), spinal cord (IC50 = 5 x 10(-8) M), rostrolateral ventricular medulla (IC50 = 10(-7) M), and nucleus tractus solitarii (IC50 = 7.5 X 10(-8) M), and by clonidine in hippocampus IC50 = 5 X 10(-8) M), spinal cord (IC50 = 4.5 x 10(-8) M), rostrolateral ventricular medulla (IC50 = 2.5 x 10( -7) M), and nucleus tractus solitarii (IC50 = 10(-7) M). This effect was counteracted by the selective alpha2-antagonists yohimbine and rauwolscine. A significant glutamate and aspartate release response was also induced by KCl (35 mmol/L) in hippocampus (+250 and + 135%, respectively) and spinal cord (+120 and +55%, respectively), in vitro. However, neither mivazerol nor clonidine, at doses up to 10 microM, had any significant effect on KCI-induced glutamate release in spinal cord, whereas mivazerol blocked completely the release of both amino acids in hippocampus and only the release of aspartate in spinal cord. On the other hand, clonidine (1 microM) was only effective in reducing by 40% the release of aspartate in hippocampus. These data indicate that (1) inhibition of KCl-induced norepinephrine release by mivazerol is mediated by its action on alpha2-adrenergic receptors; (2) at concentrations selective for alpha2-adrenergic receptors, only mivazerol was effective in blocking the KCl-induced glutamate release in hippocampal tissue; and (3) at the same concentrations, both mivazerol and clonidine were unable to inhibit glutamate release in the spinal cord. These data suggest that prevention of hyperadrenergic activity by mivazerol in perioperative patients may be mediated through its effect on the release of norepinephrine and/or the release of glutamate and aspartate in regions of the CNS that are involved in the control of cardiovascular homeostasis.

Adrenergic alpha-Agonists↗
PubMed1995

Effects of immobilization stress on hippocampal monoamine release: modification by mivazerol, a new alpha 2-adrenoceptor agonist.

Mivazerol is a new and selective alpha 2-adrenoceptor agonist which has demonstrated anti-ischemic effects, both in animals and in patients with myocardial ischemia. In the present study, mivazerol was evaluated for its ability to inhibit the release of catecholamines and serotonin (5-HT) in the hippocampus of freely moving rats, and also was compared to clonidine. In vivo microdialysis in combination with high-performance liquid chromatography (HPLC) was employed. Intravenous administration of mivazerol (8.0 micrograms/kg) had no effect on basal outflow of norepinephrine (NE), dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In contrast, clonidine (8.5 micrograms/kg, i.v.) attenuated the basal release of DOPAC, which has been proposed to reflect NE biosynthesis, suggesting that clonidine has an inhibitory effect on NE synthesis. In addition, both mivazerol and clonidine decreased the spontaneous release of 5-HT, which provided further evidence that alpha 2-adrenoceptors in the hippocampus modulate 5-HT. Sixty-min immobilization stress significantly increased the release of NE (177 +/- 28%), DA (209 +/- 46%) and DOPAC (337 +/- 72%). Mivazerol (2.5, 8.0 and 25 micrograms/kg, i.v.) completely prevented the immobilization stress-induced enhancement of NE, DA and DOPAC, which was equi-effective to clonidine at a dose of 8.5 micrograms/kg, i.v. These findings demonstrate that mivazerol has a profound modulatory effect on stress-induced neurotransmitter release in the hippocampus, at dose levels reported to protect against myocardial ischemia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

The use of the rat iris as a model system to evaluate the effect of the cholinotoxin, AF64A, in vivo.

The iris is innervated by both cholinergic parasympathetic, and adrenergic sympathetic branches of the autonomic nervous system. This innervation represents a simple and anatomically well-defined system to evaluate the effects of chemical compounds on cholinergic and adrenergic neurons. AF64A (acetyl ethylcholine aziridinium) is a known cholinotoxin in the brain and, in these experiments using the iris system, we evaluated its in vivo effect on cholinergic enzyme activity, pupillary size, and catecholamine neurotransmitter levels. We found in this system that AF64A reduces the activity of choline acetyltransferase (ChAT) but not acetylcholinesterase (AChE). AF64A is selective for cholinergic neurons, since norepinephrine and dopamine levels were unaffected.

Acetylcholinesterase↗
PubMed1995

Within-subject decline in delayed-non-match-to-sample radial arm maze performance in aging Sprague-Dawley rats.

A within-subject design was used to examine delayed-non-match-to-sample radial arm maze performance in aging (6-18 months) male Sprague-Dawley rats. A decrease in correct choices and an increase in retroactive errors were observed at all retention intervals at 18 months of age compared with performance at 6 or 12 months. No age by retention interval interaction was observed. Neither age nor increasing retention interval influenced proactive errors during the retention test. The observation of an age- and delay-dependent increase in retroactive errors, but not proactive errors, suggests that the deficit relates to a memory dysfunction as opposed to a generalized performance deficit.

Aging↗