Relative medial and dorsal cortex volume in relation to foraging ecology in congeneric lizards

The need to locate distributed resources such as mates, food, and nests is correlated with an enlarged hippocampus in many mammalian and avian species. This correlation is believed to be a consequence of selection for spatial ability. Little is known about how such ecological needs affect non-mammalian, non-avian species. In lizards, the putative hippocampal homologues are the dorsal cortex (DC) and medial cortex (MC). We examined the relationship between foraging ecology and the size of the DC and MC in congeneric male lizards. We predicted based on the mammalian and avian literature that Acanthodactylus boskianus, an active forager that captures clumped, immobile prey would have a larger MC and DC than A. scutellatus, a sit-and-wait predator, that captures mobile prey. Our previous behavioral studies showed that A. boskianus did not differ from A. scutellatus on a spatial task but that A. boskianus was significantly better at the reversal of a visual discrimination, another task that is hippocampally dependent in mammals. In the current study, we found that, relative to telencephalon volume, the MC and DC were larger in the active forager whereas a control region, the lateral, olfactory, cortex, was similar in size between species. The current anatomical results suggest that MC and DC size is related to active foraging in lizards and, along with our previous behavioral studies, show that it is possible for this relationship to occur in the absence of evidence for species differences in spatial memory. Copyright (R) 2000 S.Karger AG, Basel     

Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region

The present study investigated the effects of naturally fluctuating endogenous levels of oestrogen on the induction and maintenance of long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. Using an anaesthetized in vivo preparation, the results showed that the induction of LTP was augmented during the pro-oestrous stage of the oestrous cycle. In contrast to LTP, however, the induction of paired-pulse LTD was severely attenuated during pro-oestrous, but was clearly manifested by rats during met/dioestrous and oestrous stages of the cycle. These findings are discussed with reference to: (i) the modulatory effects of oestrogen on N-methyl-D-aspartate (NMDA) receptor function and gamma-aminobutyric acid (GABA) neurotransmission in the hippocampus; and (ii) the functional implications that such cyclical changes in synaptic plasticity have for learning and memory processes supported by the hippocampus.     

Stereoselective and substrate-dependent inhibition of hepatic mitochondria beta-oxidation and oxidative phosphorylation by the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen, and ketorolac

Non-steroidal anti-inflammatory drugs (NSAIDs) cause a range of adverse effects, some of which have been associated with perturbances of lipid metabolic pathways. Previous data demonstrating stereoselective formation of the CoA thioester of R-ibuprofen in particular were suggestive of possible stereoselective effects on lipid metabolism. Our aim was to characterise the relative stereoselectivity of the effects of ibuprofen, flurbiprofen, and ketorolac (0.01-1.0 mM) on both the beta-oxidation of palmitate and oxidative phosphorylation in rat hepatic mitochondria as a means of dissecting prostaglandin related from non-prostaglandin-related events. Beta-oxidation was inhibited stereoselectively by R-ibuprofen (P = 0.015), non-stereoselectively by R- and S-flurbiprofen (P = 0.002 and P = 0.004, respectively), and was essentially unaffected by either enantiomer of ketorolac. At 0.25 mM, inhibition by R-ibuprofen and both flurbiprofen enantiomers was partially reversed by increasing CoA concentrations (0-200 microM). Mitochondrial respiration was moderately inhibited by both enantiomers of ibuprofen and flurbiprofen (P < 0.01), but only by high concentrations (> or = 1 mM) of the enantiomers of ketorolac (P < 0.01). Uncoupling of oxidative phosphorylation measured as stimulation of State 4 respiration contributed to these effects. The data support interactions involving both stereoselective CoA-dependent and non-CoA-dependent mechanisms. The plasma drug concentrations required to achieve these effects are not likely to be attained in the majority of patients, although these concentrations are achievable in the gastrointestinal tract and may contribute to the well-known spectrum of adverse effects in this organ. Some patients do experience systemic adverse events which may be mediated by these mechanisms.     

The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.     

Antihyperglycaemic effect of saccharin in diabetic ob/ob mice

1. The effect of chronic saccharin (benzosulphimide) consumption on glucose homeostasis was examined in normal lean +/+ mice and genetically obese hyperglycaemic insulin-resistant ob/ob mice.
2. Consumption of a 5% (w/v) sodium saccharin solution for 7 weeks prevented the development of hyperglycaemia, improved glucose tolerance (area under curve decreased by 51%), reduced the extent of hyperinsulinaemia (by 21%), and reduced excessive weight gain (by 18%) in ob/ob mice.
3. Consumption of 5% (w/v) sodium saccharin temporarily decreased hyperphagia at the beginning of treatment, decreased hepatic glycogen content (by 47%), increased abdominal muscle glycogen content (by 82%), but did not significantly alter the hypoglycaemic response to exogenous insulin in ob/ob mice.
4. Consumption of a 1% (w/v) sodium saccharin solution did not prevent the development of hyperglycaemia in ob/ob mice.
5. Normal lean +/+ mice consuming 5% (w/v) sodium saccharin solution showed a marginal decrease (by 8%) in glycaemia, and glucose tolerance was improved (area under curve decreased by 30%) without a significant change in the insulin response to glucose or the hypoglycaemic effect of exogenous insulin.
6. The results suggest that chronic consumption of saccharin can defer the development of hyperglycaemia and improve glucose homeostasis in insulin-resistant ob/ob mice through a mechanism that is independent of insulin.

     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA

• 1 It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.
• 2 The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region.
• 3 It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.
• 4 It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.

     

Extradural total petrous apex resection with trigeminal translocation for improved exposure of the posterior cavernous sinus and petroclival region

We have analyzed a strategy for improved exposure of the posterior cavernous sinus and petroclival region through an extradural subtemporal approach to be utilized in the removal of neoplastic processes with involvement of the apical petrous bone and posterior cavernous sinus. This surgical approach includes the following elements for improved exposure of the posterior cavernous sinus through the middle fossa corridor: (1) maximal extradural exposure and mobilization of the trigeminal nerve complex, allowing its elevation and anterior displacement, (2) complete extradural removal of the anterior petrous pyramid from the porus acousticus to the petrous apex under direct vision, (3) total exposure of the abducens nerve from the posterior fossa to its point of cross over the intracavernous carotid artery, and (4) wide extradural exposure of the cavernous carotid artery in the foramen lacerum region. This strategy can be combined with other related approaches; specifically, frontotemporal or posterior transpetrosal exposures for extensive lesions.Microsurgical dissection and morphometric analysis were performed in 20 fixed cadaver specimens for the purposes of validating the method for clinical application and determining the key elements to maximization of exposure. The trigeminal complex could be anteromedially retracted 4.8 mm +/- 1.3 (range = 3 to 6 mm) without skeletonization of V(2) and V(3). Liberating these two divisions from their bony canals to their first peripheral branch (10.4 mm +/- 2.5 and 5.4 mm +/- 1.1, respectively) resulted in increased mobilization an average of 9.1 mm +/- 1.7 (7 to 14 mm). Further mobilization is achieved by dividing the attachment between the trigeminal connective tissue sheath and the fibrous carotid ring at the foramen lacerum. An average of 13.0 mm +/- 3.1 (7 to 20 mm) of the posterior intracavernous carotid artery was exposed. Detailed microanatomic observations and a comprehensive morphometric analysis of the relevant anatomic relationships were made.     

Human tumor cell strains defective in the repair of alkylation damage

We have previously identified four human astrocytoma cell strainsas defective in the repair of N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) damaged adenovirus 5. We now show that two of these strains(the only two tested), in comparison to other tumor strainsor normal human skin fibroblasts, are very sensitive to MNNG-producedkilling as measured by colony forming ability, but are normallysensitive to ultraviolet light. Further, such repair deficientcells may be cultured from tumors of the colon, lung, skin,and neck. The phenotype of deficient repair of MNNG-treatedadenovirus 5 has now been found in a subgroup of 9 of the 39human tumor strains tested. We propose to call this phenotypethe Mer^– phenotype. None of the 22 strains of normal humanskin fibroblasts tested showed deficient repair of MNNG damage.MNNG treatment (80 µM) causes a decrease in semi-conservativeDNA synthesis from which Mer^– tumor cells do not recover,but from which cells capable of normal repair of MNNG damage(Mer⁺) do. Somewhat paradoxically, Mer^–cells show moreMNNG-stimulated DNA synthesis (‘repair synthesis’)than do Mer⁺ cells. Besides being deficient in the repair ofMNNG-damaged adeno-viruses Mer– cells also have difficultyin repairing viruses damaged either by other N-alkyl-N'-nitro-N-nitrosoguanidines,or by N-methyl- or N-ethyl-N-nitrosoureas.