Lack of effects of prenatal exposure to lidocaine on development of behavior in rats

The objective of this investigation was to study the effects of lidocaine upon postnatal development of the rat. Lidocaine, 6 mg/kg (21 mumol/kg), was given to a group of 12 rats. Injections were administered intramuscularly, bilaterally in the masseter muscles, once a day on days 10 and 11 of pregnancy. Twelve control rats were given physiologic saline. Clinical signs, mortality, body weight, and food consumption were recorded during pregnancy and lactation. The duration of gestation was also recorded. The development of the offspring was monitored by tests of spontaneous activity, nociception, learning ability, and physical development. No clinical signs of adverse reactions were seen in any of the groups. In the majority of the learning ability tests, the control and lidocaine-treated groups showed similar results. However, in the schedule of differential reinforcement of low rates of responding (DRL 20), the lidocaine-exposed males received more reinforcements than the controls and made fewer responses. In the tests of nociception, a significant difference between sexes was recorded, in that the females were more sensitive than the males in the shock-titration test. Physical development, as monitored by swimming ability and spontaneous activity, showed no inter-group difference. The present results indicate that prenatal exposure to lidocaine fails to result in postnatal impairment of the development of behavioral performance of a wide range of tasks.     

Neuropsychological changes during steady-state drug use,withdrawal and abstinence in primary benzodiazepine-dependent patients

Impairment on neuropsychological tests during steady-state drug use and withdrawal, and after discontinuation of benzodiazepines, was studied in primary benzodiazepine-dependent patients. One group of patients was tested before and the other group after the initiation of a gradual tapering-off of the drug, and both groups were tested approximately 1 year later. At the initial assessment, both groups of patients showed impairment on most of the tests of general intelligence and on several of the tests in the Halstead-Reitan battery, as well as on a test of nonverbal memory, in comparison with healthy controls. At follow-up the patient groups had reached the level of the control group. This study confirmed earlier observations of neuropsychological deficits in long-term benzodiazepine-using patients and demonstrated that these changes are at least partly reversible by discontinuing drug intake.     

Acute tolerance to ethanol using drug discrimination and open-field procedures in rats

This study examined the phenomenon of acute tolerance to ethanol (ETOH) using drug discrimination learning (DDL), and open-field (OF) procedures. In DDL, rats were trained to discriminate between ETOH (1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9 g/kg), or higher (1.8 and 2.4 g/kg) than the training dose were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations after different ETOH doses were achieved by postponing the tests until sufficient time had elapsed. Only doses of ETOH higher than the training dose produced acute tolerance in the DDL procedure. For the response-time data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for different spontaneous behaviours in drug-naive animals. At equal ETOH concentrations, the group examined during the descending phase of intoxication (1.8 g/kg, 60 min post-injection), reared significantly more than the group tested during the ascending phase (1.5 g/kg, 10 min post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is suggested that acute tolerance is seen both in ETOH naive and in ETOH pre-exposed rats. However, in DDL acute tolerance was observed only when doses higher than the training dose of ETOH were evaluated.     

Composition of the Essential Oil of Agastache foeniculum

AGASTACHE FOENICULUM contains 0.1-0.3% essential oil and the main components are limonene, beta-caryophyllene, methylchavicol, and germacrene B (92% altogether). In addition 35 components, each accounting for less than 1% of the total essential oil, were identified.     

Absence of association between an intercellular adhesion molecule 1 gene E469K polymorphism and Alzheimer's disease in Finnish patients

Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.     

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.     

A mouse model for alpha-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids

alpha-Methylacyl-CoA racemase (Amacr) deficiency in humans leads to sensory motor neuronal and liver abnormalities. The disorder is recessively inherited and caused by mutations in the AMACR gene, which encodes Amacr, an enzyme presumed to be essential for bile acid synthesis and to participate in the degradation of methyl-branched fatty acids. To generate a model to study the pathophysiology in Amacr deficiency we inactivated the mouse Amacr gene. As per human Amacr deficiency, the Amacr(-/-) mice showed accumulation (44-fold) of C27 bile acid precursors and decreased (over 50%) primary (C24) bile acids in bile, serum and liver, however the Amacr(-/-) mice were clinically symptomless. Real-time quantitative PCR analysis showed that, among other responses, the level of mRNA for peroxisomal multifunctional enzyme type 1 (pMFE-1) was increased 3-fold in Amacr(-/-) mice. This enzyme can be placed, together with CYP3A11 and CYP46A1, to make an Amacr-independent pathway for the generation of C24 bile acids. Exposure of Amacr(-/-) mice to a diet supplemented with phytol, a source for branched-chain fatty acids, triggered the development of a disease state with liver manifestations, redefining the physiological significance of Amacr. Amacr is indispensable for the detoxification of dietary methyl-branched lipids and, although it contributes normally to bile acid synthesis from cholesterol, the putative pMFE-1-mediated cholesterol degradation can provide for generation of bile acids, allowing survival without Amacr. Based upon our mouse model, we propose elimination of phytol from the diet of patients suffering from Amacr deficiency.