Neuronal cell deficits following maternal exposure to methadone in rats

Summary Rat offspring were maternally subjected to methadone hydrochloride during gestation or lactation. At 21 days of age, the area of the pyramis (cerebellar lobule VIII) in prenatally and postnatally exposed groups was reduced 45% and 36%, respectively, from control levels, and the total number of internal granule neurons/section was reduced 49% and 46%, respectively; the number of granule neurons/mm² in both groups was 75% of control values. Based on histological evaluation the timetable of cerebellar morphogenesis was unaltered in rats prenatally exposed to methadone, suggesting a permanent neuronal deficit, but cerebellar development was markedly delayed in animals subjected postnatally.This work was supported by National Institute on Drug Abuse grant DA-01618.     

Effect of adrenalectomy on sound-induced seizure susceptibility and intensity in genetically susceptible rats

Summary Neither seizure susceptibility nor intensity was altered by sham-operation or by adrenalectomy in adult rats that are genetically susceptible to sound-induced seizures. Thus, sound-induced seizures in genetically susceptible rats are analogous to those in genetically susceptible mice to the extent that removal of the adrenal glands does not alter established seizure characteristics in either species.     

Myelination in the hippocampus during development and following lesion

Myelin is crucial for the stabilization of axonal projections in the developing and adult mammalian brain. However, myelin components also act as a non-permissive and repellent substrate for outgrowing axons. Therefore, one major factor which accounts for the lack of axonal regeneration in the mature brain is myelin. Here we report on the appearance of mature, fully myelinated axons during hippocampal development and following entorhinal lesion with the myelin-specific marker Black Gold. Although entorhinal axons enter the hippocampal formation at embryonic day 17, light and ultrastructural analysis revealed that mature myelinated fibers in the hippocampus occur in the second postnatal week. During postnatal development, increasing numbers of myelinated fibers appear and the distribution of myelinated fibers at postnatal day 25 was similar to that found in the adult. After entorhinal cortex lesion, a specific anterograde denervation in the hippocampus takes place, accompanied by a long-lasting loss of myelin. Quantitative analysis of myelin and myelin breakdown products at different time points after lesion revealed a temporally close correlation to the degeneration and reorganization pha-ses in the hippocampus. In contrast, electroconvulsive seizures resulted in brief demyelination and a faster recovery time course. In conclusion, we could show that the appearance of mature axons in the hippocampus is temporally regulated during development. In the adult hippocampus, demyelination was found after anterograde degeneration and also following seizures, suggesting that independent types of insult lead to demyelination. Reappearing mature axons were found in the hippocampus following axonal sprouting. Therefore, our quantitative analysis of mature axons and myelination effectively reflects the readjusted axonal density and possible electrophysiological balance following lesion. Received 22 December 2003; received after revision 11 February 2004; accepted 17 February 2004     

Angiotensin II in the hippocampus. A histochemical and electrophysiological study

Summary The presence of the renin angiotensin system in the hippocampus is shown by immunohistochemistry. Intra- and extra-cellular recordings revealed that angiotensin II and III excite CA 1 pyramidal cells by disinhibition. The effect is antagonized by [Sar¹, Thr⁸]-A II.This work was supported by grant Nos 3.271.78 and 3.396.78 of the Swiss National Science Foundation and research grant HL-24112 from NIH. T. Inagami was a visiting scientist of the Roche Medical Research Foundation.     

The control of amygdaloid seizures by the globus pallidus

Summary Both in acute and chronic cats entopeduncular stimulation inhibits, to a greater extent than caudate activation, focal paroxysmal activity in the ventro-basal complex of the amygdala. Lesion of entopeduncular neurons, by means of kainic acid injection, induces a decrease of the caudate inhibitory effect. It is suggested that neostriatal control of the amygdaloid seizures occurs partly through the globus pallidus.This work was supported by a grant from the Consiglio Nazionale delle Ricerche, Roma, Italy.     

Cholinomimetics produce seizures and brain damage in rats

Microinjections of the cholinergic agonists, carbachol and bethanechol, either into the amygdala or into the dorsal hippocampus produced sustained limbic seizures and brain damage in rats. Systemic administration of pilocarpine in rats resulted in a sequence of convulsive disorders and widespread brain damage as well. Scopolamine prevented the development of convulsive activity and brain damage produced by cholinomimetics. These results suggest that the excessive stimulation of cholinergic muscarinic receptors can lead to limbic seizures and brain damage. It is postulated that muscarinic cholinergic mechanisms are linked to the etiology of temporal lobe epilepsy and epileptic brain damage.     

Altered axon terminals containing concentric lamellar bodies of cerebellar Pukinje cells in Mongolian gerbil

Altered axon terminals containing concentric lamellar bodies were observed in cerebellar and vestibular nuclei of the Mongolian gerbil. The terminals increased in number from 30 days of age onward, and reached about tenfold at 360 days. The numbers were the same in two gerbil strains with different susceptibility to spontaneous motor seizures by various stimuli, but about threefold those in Slc:Wistar rat.     

Correlation between the susceptibility of E. coli to phagocytosis and their ability to invade HeLa cells in vitro

Summary The susceptibility of several strains of E. coli to phagocytic killing by polymorphonuclear leucocytes and the ability of the same strains to invade HeLa cells were studied. It was found that only the strains resistant to killing by leucocytes were able to penetrate and multiply within HeLa cells.Acknowledgments. We thank Dr Bianca Pani who supplied us with HeLa cells. Supported by grant No. 75.00695.04 from the National Research Council of Italy (CNR).     

Epileptogenic action of intra-amygdaloid injection of kainic acid]

Intra-amygdaloid unilateral application of low doses of kainic acid rapidly elicits, in both chronic and acute conditions, secondarily generalized convulsive seizures which often culminate in fatal true status epilepticus unless appropriate anti-epileptic drugs are provided. Spontaneous recurrent seizures are observed for several hours starting approximately 10 min. after the application of kainic acid. In addition to the primary degeneration in the amygdaloid complex, a secondary cell loss is seen in CA3 area of the dorsal hippocampus. It is suggested that this procedure may constitute a particularly suitable model for the study of true focalized status epilepticus.     

Effect of stress on choline acetyltransferase activity of the brain and the adrenal of the rat

Choline acetyltransferase (ChAT) activity was determined in cerebral cortex, hypothalamus, hippocampus, cerebellum, medulla oblongata, midbrain and adrenal gland of rats exposed to acute or chronic stress. The exposure of animals to acute immobilization and cold stress (4°C) for one hour resulted in a significant decline of ChAT activity in all brain regions examined except for the medulla oblongata. Moreover, the exposure to acute stress resulted in significant increase of the same enzyme in the adrenal gland. However, chronic exposure of animals to cold stress (4°C) for 7 days resulted in no significant changes of ChAT activity in all tissues examined except for a decline in the midbrain and an increase in the medulla oblongata. The administration of corticosterone (2.0 mg/kg) 1 h prior to sacrificing caused an effect similar to that of acute stress on ChAT activity in all brain regions except for the hypothalamus and the cerebellum. It was concluded from this experiment that stress-induced changes in the ChAT activity of specific brain regions might be mediated by the adrenal steroids.This work was supported by a grant from the National Aeronautics and Space Administration (NSG 2183 and NAG 2-411), a grant from the National Institutes of Health (NIH RR 0811) and a grant from the Division of Research Resources (NIH grant RR 03020).     

The effect of physostigmine on (Na++K+)-ATPase activity in different rat brain regions

Summary The activity of (Na⁺+K⁺)-ATPase and acetylcholine esterase were folloed in rat brain cerebral cortex, caudate, thalamus, hippocampus and medulla after i.v. administration of physostigmine. Both enzymes were found to be inhibited in a dose-dependent manner. The most pronounced inhibition of (Na⁺+K⁺)-ATPase was found in caudate. where the highest activity of acetylcholine esterase is found.These studies were supported by a grant from the Union of Science of Republic Serbia, No. 40404-14.     

Nuclear localization of aldosterone in rat brain cells assessed by autoradiography

Summary Autoradiographic studies with³H aldosterone demonstrate nuclear concentration of hormone in neurons of the hippocampus, septum, allocortical regionss and brain stem reticular formation and motor nuclei of cranial nerves and in the meninges. The results suggest that mineralocorticoids have wide ranging effects on different parts of the central nervous system.This work was supported by the Medical Research Council of Canada and by PHS grant NS09914. We thank Ms Brenda McClain for technical assistance.     

Deficits in synapse-to-neuron ratio due to early undernutrition show evidence of catch-up in later life

Summary 30-day-old rats undernourished from birth are known to have large deficits in the synapse-to-neuron ratio in certain brain regions. It has not been possible to demonstrate any statistically significant deficits in this ratio in animals undernourished from birth to 30 days but then provided with an ad libitum amount of food till 6 months of age.Acknowledgments. This work was supported by the Medical Research Council and the National Fund for Research into Crippling Diseases.     

Mutagenicity of melanin from human red hair

Summary TheSalmonella typhimurium histidine reversion test of Ames et al. was used to demonstrate that pheomelanin, the red-brown polymeric pigment produced in human skin and hair, becomes mutagenic after exposure to long wave-length UV-light; a finding consistent with the UV-induced somatic mutation hypothesis for the origin of freckles and the high susceptibility of redheads and blonds to sunlight-induced skin cancers.Acknowledgments.S. typhimurium strains were kindly provided by Dr Bruce N. Ames. Z. Harzanyi was supported by NIEHS grant 00675-03 and an Andrew W. Mellon Teacher-Scientist Award. M. Chedekel thanks The Ohio State University Graduate School for financial assistance.     

Influence of the pineal gland on the reproductive system of the male house mouse

Summary Procedures designed to express pineal-mediated antigonadotropic activity were performed upon male house mice. Neither blinding nor blinding plus olfactory bulbectomy of house mice resulted in testicular involution within 12 weeks. The pineal gland appears to be of little significance to reproduction in the house mouse.Supported by NICHHD grant No. HDO 7119-092.Supported by NICHHD grant No. 5P5 OHDO 8338.Supported by NSF grant No. SPI 7922 372.     

Is the variation in the susceptibility of various species to atherosclerosis due to inborn differences in prostacyclin (PGI2) formation?

Summary Species exhibiting a higher susceptibility to the development of atherosclerosis have a reduced prostacyclin (PGI₂)-generation in the arterial wall, which differs in various parts of the vascular system. As the difference in PGI₂-formation in various diseases is a generalized vascular effect, the changes can be detected in all vessels. This is a very important point for diagnostic purposes in humans.This study was supported by a grant of the «Fonds 600 Jahre Wiener Universität der Kammer der gewerblichen Wirtschaft für Wien».     

The involvement of noradrenaline, 5-hydroxytryptamine and acetylcholine in imipramine-induced seizures in mice

The influence of some noradrenergic, 5-hydroxytryptaminergic and cholinergic agents on imipramine-induced seizures were investigated in mice. DL-threo-3,4-dihydroxyphenylserine (DOPS) and pargyline significantly potentiated imipramine-induced seizures. Phentolamine and prazosin significantly attenuated seizures elicited by imipramine and significantly attenuated the seizure-enhancing effect of DOPS. -Methyl-p-tyrosine and reserpine significantly attenuated seizures induced by imipramine. Disulfiram significantly protected mice against imipramine-induced seizures. However, DOPS significantly potentiated seizures induced by imipramine in disulfiram-pretreated animals. Clonidine effectively protected mice against imipramine-induced seizures. Idazoxan, on the other hand, significantly protentiatied seizures induced by imipramine and significantly antagonised the protective effect of clonidine against the seizures. 5-HTP, PCPA, cyproheptadine, mianserin, ketanserin and trazodone did not affect imipramine-induced seizures to any significant extent. Physostigmine antagonised seizures induced by imipramine while atropine significantly potentiated the seizures, and significantly attenuated the protective effect of physostigmine against the seizures. These data suggest that enhancement and attenuation of central noradrenergic and cholinergic neurotransmissions respectively, and not 5-HT mechanisms, may underlie imipramine-induced seizures in mice.     

Microbial methylation of benzenethiols and release of methylthiobenzenes

Summary Three phylogenetically diverse microorganisms methylated several different chloro- and nitro-substituted benzenethiols to yield the corresponding methylthiobenzenes. These products were identified by gas chromatography-mass spectrometry. In several cases large percentages of the methylthio products were released by intact cells into the medium, suggesting that microbial methylation of xenobiotic thiols may be a significant biotransformation in many ecosystems.Acknowledgments. This investigation was supported by research grant ES 02639 from the National Institute for Environmental Health Sciences, and an equipment grant (RR07013) from the Biomedical Research Support grant program. Division of Research Resource, NIH. We thank Steve Hawthorne for assistance in performing GC-MS analyses.     

Galanin – 25 years with a multitalented neuropeptide

Neuroanatomical localization and physiological properties of galanin suggest that the peptide may be involved in the regulation of seizures. Indeed, administration of galanin receptor agonists into brain areas pertinent to the initiation and propagation of epileptic activity attenuated seizure responses under conditions of animal models of epilepsy; pharmacological blocking of galanin receptors exerted proconvulsant effects. Functional deletion of both galanin and galanin type 1 receptor genes produced transgenic mice with either spontaneous seizure phenotype, or with enhanced susceptibility to seizure stimuli. At the same time, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection techniques, hindered the epileptic process. Galanin exerts anticonvulsant effects through both type 1 and type 2 receptors, with distinct downstream signaling cascades. Several synthetic agonists of galanin receptors with optimized bioavailability have been synthesized and inhibited experimental seizures upon systemic administration, thus opening an opportunity for the development of galanin-based antiepileptic drugs.     

Binding capacities of various analogues of S-adenosyl-L-homocysteine to protein methyltransferase II from human erythrocytes

Summary A series of analogues of S-adenosyl-L-homocysteine, modified mainly in the amino acid portion of the molecule, have been synthesized. All were found to be competitive inhibitors of protein methyltransferase II from human erythrocytes. S-adenosyl-L-homocysteine remains however by far the most effective inhibitor of the methylase.Acknowledgments. This work was supported by a grant of the Fonds National Belge de la Recherche Scientifique and by a grant of the Fonds Emile Defay.