The aging brain, a key target for the future: The protein kinase C involvement

The brain represents the primary centre for the regulation and control of all our body activities, receiving and interpreting sensory impulses and transmitting information to the periphery. Most importantly, it is also the seat of consciousness, thought, emotion and especially memory, being in fact able to encode, store and recall any information. Memory is really what makes possible so many of our complex cognitive functions, including communication and learning, and surely without memory, life would lose all of its glamour and purpose. Age-associated mental impairment can range in severity from forgetfulness at the border with pathology to dementia, such as in Alzheimer's disease. In recent years, one of the most relevant observations of research on brain aging relates to data indicating that age-related cognitive decline is not only due to neuronal loss, as previously thought; instead, scientists now believe that age-associated functional changes have more to do with the dysfunctions occurring over time. Within this context a prominent role is certainly played by signal transduction cascades which guarantee neuronal cell to elaborate coordinated responses to the multiple signals coming from the outside and to adapt itself to the environmental changes and requests. This review will focus the attention on protein kinase C pathway, with a particular interest on its activation process, and on the role of protein-lipid and protein-protein interactions to selectively localize the cellular responses. Furthermore, information is emerging and will be discussed on the possibility of mRNA stabilization through PKC activation. This review will also approach the issue on how alterations of these molecular cascades may have implications in physiological and pathological brain aging, such as Alzheimer's disease.     

Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood-brain barrier.

PURPOSE: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood-brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). METHODS: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. RESULTS: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. CONCLUSIONS: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile.     

Isolated intracranial hypertension due to Lyme's disease]

Lyme's borreliosis is characterized by the variety of its revealing symptoms, which may explain an often delayed diagnosis. We report on a case of a child affected by Lyme's disease, confirmed by serology, who presented a particular form consisting in an isolated intracranial hypertension. This rare form must be known and diagnosed early in order to avoid serious complications such as optic nerve atrophia in the absence of an appropriate treatment.     

Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study.

We sought whether microdamage could rise in postmenopausal osteoporotic women on long-term bisphosphonates, as suggested by recent animal studies. We found few microcracks in iliac bone biopsies, despite a marked reduction in bone turnover. INTRODUCTION: Animal studies suggest that bisphosphonates (BPs) could increase microdamage frequency in a dose-dependent manner, caused by excessively suppressed bone turnover. However, there is limited data in humans receiving BP therapeutic doses for >3 yr. MATERIALS AND METHODS: We measured microcrack frequency and histomorphometry parameters on transiliac bone biopsies in 50 postmenopausal osteoporotic women (mean age = 68 yr) who had received BP therapy (3 on intravenous pamidronate, 37 on oral alendronate, and 10 on oral risedronate) for at least 3 yr (mean treatment duration = 6.5 yr). We compared these results with transiliac bone biopsies obtained from 12 cadavers. We used bulk staining with green calcein as a fluorochrome. The microcracks were quantified in three 100-microm-thick sections using optic microscopy and were confirmed by laser confocal microscopy. Microcrack frequency (number of microcracks/mm2 of bone tissue) was compared between treated women and controls using nonparametric tests. We also explored predictors of microcrack frequency, including age, duration of BP therapy, and activation frequency. RESULTS: Among treated women, cancellous bone microcrack frequency was low (mean, 0.13 microcracks/mm2) and did not differ significantly from that observed in controls (0.05 microcracks/mm2; p = 0.59). Of note, 54% of the treated women and 58% of the controls had no observable microcracks. There was no association between microcrack frequency and the duration of BP therapy (for microcracks/mm2 and duration, Spearman r = 0.04, p = 0.80) and between patients' ages and the number of microcracks (Spearman r = -0.09, p = 0.61). Although bone remodeling parameters were suppressed in treated women, we found no relationship between microcrack density and activation frequency (Spearman r = -0.003, p = 0.99). Also, microcrack frequency was not increased in women with prevalent vertebral fracture compared with those without fractures. CONCLUSIONS: Among postmenopausal osteoporotic women on long-term BPs, microcrack frequency in the iliac bone is low, despite a marked reduction of bone turnover.     

Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography.

Studies of central benzodiazepine receptors in the human brain in vivo are now possible using positron emission tomography (PET) and [11C]flumazenil. With the aim of measuring Bmax and Kd in brain regions, we used a two-injection [11C]flumazenil (at high and low specific radioactivity, respectively) pseudo-equilibrium paradigm to evaluate, in seven unmedicated healthy volunteers, the relative merits of three 'reference' structures (pons, hemispheric white matter and corpus callosum) in which the free radioligand concentration in brain tissue was estimated 15-40 min after i.v. injection of the radioligand. By means of high-resolution PET, the Bmax and Kd were calculated for each subject in 18 gray matter structures, based on a two-point Scatchard plot. We found that the use of the corpus callosum as reference often resulted in spurious Bmax and Kd values. The pons was the best reference structure because it provided satisfactory Bmax values (closest to in vitro data) and most consistent Kd values, and was the region easiest to sample on PET images. The pattern of regional Bmax was consistent with that expected from in vitro studies, with values highest in the cerebral cortex, intermediate in the cerebellum, and lowest in the striatum and the thalamus. The Kd values were uniform among regions and were consistent with earlier in vitro and in vivo data. This work documents the feasibility of estimating Bmax and Kd of central benzodiazepine receptors in multiple brain regions for clinical research.