Intraocular 6-hydroxydopamine prevents the persistent estrus induced by continuous light

Following the intraocular injection of 6-hydroxydopamine, which can destroy the retinal dopaminergic neurons, female rats showed a normal estrous cycle in LD 12:12 but not a persistent estrus in continuous light.     

The effect of L-Dopa on the spinal monosynaptic mass reflex

Summary After i. v. injection of reserpine, the monosynaptic mass reflex (MSMR) is depressed in spinalized cats. However, the complete recovery of MSMR was obtained 30 min after L-Dopa application. Pimozide, a dopamine-receptor blocking agent, blocked this action of L-Dopa. It is presumed that dopaminergic receptors are involved in the action of L-Dopa on spinal MSMR.     

Intraocular 6-hydroxydopamine prevents the persistent estrus induced by continuous light

Summary Following the intraocular injection of 6-hydroxydopamine, which can destroy the retinal dopaminergic neurons, female rats showed a normal estrous cycle in LD 1212 but not a persistent estrus in continuous light.     

The effect of L-dopa on pupillary diameter in mice

Summary Injection of L-dopa in mice produces dose-dependent mydriasis. Pre-treatment with peripheral dopa-decarboxylase inhibitors (carbidopa and benserazide) or with an alpha-adrenergic blocking agent (phentolamine) abolishes the pupillary dilation caused by L-dopa. Pretreatment with fusaric acid, an inhibitor of dopamine-beta-hydroxylase, also antagonizes the mydriatic effect of L-dopa. Thus, our results suggest that the mydriasis produced in mice following the injection of L-dopa is caused by its peripheral conversion to noradrenaline, which stimulates alpha-adrenergic receptors in the dilator iridis. There was no evidence that stimulation of specific dopaminergic receptors was involved.We are grateful to N. Rothschild, Head of Laboratory Animal Department, Sackler School of Medicine, for his help.     

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis

Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism by which this occurs, the effects of intracerebroventricular (icv) injection of human recombinant IL-1β on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. Icv injection of IL-1 produced a rapid rise of the tissue mRNA levels of IL-6 and TNF in both organs, prior to and/or in parallel with an increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the IL-6 responses, while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6, but not of TNF, through autonomic nervous system activation. Received 27 October 1997; received after revision 15 December 1997; accepted 12 January 1998     

Depressor effects of muscarinic and non-muscarinic mediation induced by lateral hypothalamic stimulation in the cat

Transient sympathetically-mediated depressor effects were induced by stimulation of a small locus in the lateral hypothalamic peri-fornical region, medial to the fields of Forel. The ganglionic blocking agent, atropine methyl nitrate (ATMN), was used to show that muscarinic as well as non-muscarinic sympathetic ganglion receptor neurotransmission was involved. Evidence is presented that stimulation of this LH site co-activates a number of mechanisms and that depending on which of these are activated, the ganglionic blocking agent ATMN may either block, reverse or potentiate the depressor effect.     

Depressor effects of muscarinic and non-muscarinic mediation induced by lateral hypothalamic stimulation in the rat

Summary Transient sympathetically-mediated depressor effects were induced by stimulation of a small locus in the lateral hypothalamic peri-fornical region, medial to the fields of Forel. The ganglionic blocking agent, atropine methyl nitrate (ATMN), was used to show that muscarinic as well as non-muscarinic sympathetic ganglion receptor neurotransmission was involved. Evidence is presented that stimulation of this LH site co-activates a number of mechanisms and that depending on which of these are activated, the ganglionic blocking agent ATMN may either block, reverse or potentiate the depressor effect.     

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

O ⁶-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O ⁶-methylguanine and O ⁶-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O ⁶-benzylguanine and O ⁶-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.     

The principal toxin of Delphinium brownii Rydb., and its mode of action.

Examination of D. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.     

Hymenin, a novel alpha-adrenoreceptor blocking agent from the Okinawan marine sponge Hymeniacidon sp

A novel bromine-containing alkaloid, hymenin, has been isolated from the Okinawan marine sponge Hymeniacidon sp. as a potent alpha-adrenoceptor blocking agent and its structure determined to be 1 on the basis of the spectral data.     

Metabolic energy requirements during teleost melanophore adaptations

Summary Inhibition of oxidative phosphorylation by 2,4-dinitrophenol or sodium cyanide promotes complete melanosome aggregation in teleost melanophores. This aggregation is not promoted via the -sympathetic receptor sites because it occurs in the presence of tolazoline hydrochloride, an -receptor blocking agent. Interpretation of these results suggests metabolic energy release is required in the centrifugal direction only.This work was supported in part by grants from the National Institutes of Health (5 T01 EY00090) and from Bell Telephone Laboratories.     

Increase in in vivo (3H) spiperone binding in the rat hippocampal formation and striatum after repeated treatment with haloperidol

Summary An increase in in vivo (³H) spiperone binding was observed in rat hippocampal formation and striatum after repeated treatment with haloperidol. This suggests that in hippocampus as well as in striatum prolonged blockade of dopaminergic transmission by a neuroleptic agent results in the development of a supersensitivity of the dopamine receptors.Acknowledgments. We wish to thank Mrs J. Krauss for skillful technical assistance, Drs Helmut Bittiger and Rainer Ortmann for helpful discussions.     

Interaction between delta-6-tetrahydrocannabinol (delta-6-THC) and lithium at the blood brain barrier in rats

Summary Neither the acute nor the chronic i.p. administration of delta-6-tetrahydrocannabinol affected the passage of lithium from blood to brain in normal rats.     

Metabolic energy requirements during teleost melanophore adaptations

Inhibition of oxidative phosphorylation by 2,4-dinitrophenol or sodium cyanide promotes complete melanosome aggregation in teleost melanophores. This aggregation is not promoted via the alpha-sympathetic receptor sites because it occurs in the presence of tolazoline hydrochloride, an alpha-receptor blocking agent. Interpretation of these results suggests metabolic energy release is required in the centrifugal direction only.     

The principal toxin ofDelphinium brownii Rydb., and its mode of action

Summary Examination ofD. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.We thank the University of Calgary, The National Research Council of Canada, and the Alberta Agriculture Department, for financial assistance.     

Demonstration of an alpha adrenergic effect on the adipocytes of dog adipose tissue]

Phentolamine, an alpha blocking agent, potentializes the adrenergical lipolytic effect of isolated fat cells of Canine omental adipose tissue when their average diameter is greater than 80 micrometers. This effect can be found also in isolated fat cells of mesenteric adipose tissue, spontaneously less sensitive with catecholamines. Phenylephrine, alpha sympathomimetic, partially inhibits the lipolytic effect stimulated by isoprenaline.     

S100A6 protein: functional roles

S100A6 protein belongs to the A group of the S100 protein family of Ca²⁺-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6’s effects. Dosage of serum S100A6 might aid in diagnosis in oncology.     

Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage

The discovery that pyridoxamine (PM) can inhibit glycation reactions and the formation of advanced glycation end products (AGEs) stimulated new interest in this B₆ vitamer as a prospective pharmacological agent for treatment of complications of diabetes. The mechanism of action of PM includes: (i) inhibition of AGE formation by blocking oxidative degradation of the Amadori intermediate of the Maillard reaction; (ii) scavenging of toxic carbonyl products of glucose and lipid degradation; and (iii) trapping of reactive oxygen species. The combination of these multiple activities along with PM safety posture it as a promising drug candidate for treatment of diabetic complications as well as other multifactorial chronic conditions in which oxidative reactions and carbonyl compounds confer pathogenicity.Received 1 March 2005; received after revision 25 March 2005; accepted 31 March 2005     

In vivo continuous electrochemical determination of dopamine release in rat neostriatum]

Polarographic micro-electrodes (carbon fiber, o. d. 8 micron) implanted in the Rat caudate nucleus, allowed a practically continuous in vivo monitoring (one measurement every 5 sec.) of the extra-cellular concentration of dopamine released by striatal dopaminergic terminals. Administration of amphetamine produced a reproducible increase of the oxidation current. This effect was suppressed after the selective degeneration of the striatal dopaminergic terminals following the injection of 6-OHDA into the substantia nigra or after inhibition of the synthesis of the amine by alpha methyl-p-tyrosin. After 5 hrs. this drug produced a 70% decrease of the oxidation current.     

Seasonal variation in peripheral blood leukocyte subsets and in serum interleukin-6, and soluble interleukin-2 and-6 receptor concentrations in normal volunteers

This study has been carried out in order to investigate seasonal variation in peripheral blood immune cells, such as leukocytes, monocytes, neutrophils, lymphocytes, CD3⁺ T, CD4⁺ T, CD8⁺ t, CD25⁺ T, CD20⁺ B, and serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and sIL-2R levels in normal volunteers. Toward this end, 26 normal volunteers (13 men, 13 women) had monthly blood samplings during one calendar year for peripheral blood count, flow cytometric enumeration of peripheral leukocyte subsets and immunoassays of IL-6, sIL-6R and sIL-2R. It was found that most of the immune variables change rhythmically during the seasons as a group phenomenon. Statistically significant yearly variations with seasonal rhythms, i.e. annual rhythms or harmonics, such as semiannual, tetramensual and trimensual rhythms, were found in the number of leukocytes, neutrophils, monocytes, lymphocytes, CD4⁺ T, CD8⁺ T, CD25⁺ T, CD20⁺ B cells, in the CD4⁺/CD8⁺ ratio, and serum IL-6 and sIL-6R levels. It is concluded that the immune system is characterized by a multifrequency time-structure with significant high-amplitude yearly variations in the number of some peripheral blood leukocyte subsets.