Concentrations In Brain Areas Research Articles

Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice.

Repurposing doxycycline for the treatment of amyloidosis has recently been put forward because of the antiaggregating and anti-inflammatory properties of the drug. Most of the investigations of the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g., prion and Alzheimer disease (AD), have been carried out in mouse models, but surprisingly no data are available regarding the concentrations reached in the brain after systemic administration. We filled this gap by analyzing the pharmacokinetic profile of doxycycline in plasma and brain after single and repeated intraperitoneal injections of 10 and 100 mg/kg, in wild-type mice and the APP23 mouse model of AD. The main outcomes of our study are: 1) Peak plasma concentrations ranged from 2 to10 μg/ml, superimposable to those in humans; 2) brain-to-plasma ratio was ∼0.2, comparable to the cerebrospinal fluid/serum ratios in humans; 3) brain Cmax 4-6 hours after a single dose was ∼0.5 (10 mg/kg) and ∼5 μM (100 mg/kg). Notably, these concentrations are lower than those required for the drug's antiaggregating properties as observed in cell-free studies, suggesting that other features underlie the positive cognitive effects in AD mice; 4) elimination half-life was shorter than in humans (3-6 vs. 15-30 hours), therefore no significant accumulation was observed in mouse brain following repeated treatments; and 5) there were no differences between doxycycline concentrations in brain areas of age-matched wild-type and APP23 mice. These data are useful for planning preclinical studies with translational validity, and to identify more reliably the mechanism(s) of action underlying the central in vivo effects of doxycycline.

Brief Social Isolation in the Adolescent Wistar-Kyoto Rat Model of Endogenous Depression Alters Corticosterone and Regional Monoamine Concentrations.

The Wistar-Kyoto rat (WKY) model has been suggested as a model of adult and adolescent depression though face, predictive and construct validities of the model to depression remain equivocal. The suitability of the WKY as a diathesis model that tests the double-hit hypothesis, particularly during critical periods of brain and behavioural development remains to be established. Here, effects of post-weaning social isolation were assessed during early adolescence (~30pnd) on behavioural despair and learned helplessness in the forced swim test (FST), plasma corticosterone levels and tissue monoamine concentrations in brain areas critically involved in depression, such as prefrontal cortex, nucleus accumbens, striatum and hippocampus. Significantly increased immobility in the FST was observed in socially-isolated, adolescent WKY with a concomitant increase in corticosterone levels over and above the FST-induced stress. WKY also demonstrated a significantly increased release and utilization of dopamine, as manifested by levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in nucleus accumbens, indicating that the large dopamine storage pool evident during adolescence induces greater dopamine release when stimulated. The serotonin metabolite 5-hydroxy-indoleacetic acid was also significantly increased in nucleus accumbens, indicating increased utilization of serotonin, along with norepinephrine levels which were also signficantly elevated in socially-isolated adolescent WKY. Differences in neurochemistry suggest that social or environmental stimuli during critical periods of brain and behavioural development can determine the developmental trajectories of implicated pathways.

Brain uptake and metabolism of the endocannabinoid anandamide labeled in either the arachidonoyl or ethanolamine moiety

IntroductionAnandamide (N-arachidonoylethanolamine) is a retrograde neuromodulator that activates cannabinoid receptors. The concentration of anandamide in the brain is controlled by fatty acid amide hydrolase (FAAH), which has been the focus of recent drug discovery efforts. Previous studies in C57BL/6 mice using [3H-arachidonoyl]anandamide demonstrated deposition of tritium in thalamus and cortical areas that was blocked by treatment with an FAAH inhibitor and that was not seen in FAAH-knockout mice. This suggested that long chain fatty acid amides radiolabeled in the fatty acid moiety might be useful as ex vivo and in vivo radiotracers for FAAH, since labeled fatty acid released by hydrolysis would be rapidly incorporated into phospholipids with long metabolic turnover periods. MethodsRadiotracers were administered intravenously to conscious Swiss–Webster mice, and radioactivity concentrations in brain areas was quantified and radiolabeled metabolites determined by radiochromatography. Results[14C]Arachidonic acid, [14C-arachidonoyl]anandamide and [14C-ethanolamine]anandamide, and also [14C]myristic acid, [14C-myristoyl]myristoylethanolamine and [14C-ethanolamine]myristoyl-ethanolamine all had very similar distribution patterns, with whole brain radioactivity concentrations of 2–4% injected dose per gram. Pretreatment with the potent selective FAAH inhibitor URB597 did not significantly alter distribution patterns although radiochromatography demonstrated that the rate of incorporation of label from [14C]anandamide into phospholipids was decreased. Pretreatment with the muscarinic agonist arecoline which increases cerebral perfusion increased brain uptake of radiolabel from [14C]arachidonic acid and [14C-ethanolamine]anandamide, and (in dual isotope studies) from the unrelated tracer [125I]RTI-55. ConclusionsTogether with our previously published study with [18F-palmitoyl]16-fluoro-palmitoylethanolamine, the data show that the primary determinant of brain uptake for these tracers in Swiss–Webster mice is initial distribution according to blood flow. It is possible that recently reported strain differences in long chain fatty acid trafficking between C57BL/6 and Swiss–Webster mice are responsible for the differences between our results using [14C]anandamide and the earlier studies using [3H]anandamide.

Subacute Pain after Traumatic Brain Injury Is Associated with Lower Insular N-Acetylaspartate Concentrations.

Persistent pain is experienced by more than 50% of persons who sustain a traumatic brain injury (TBI), and more than 30% experience significant pain as early as 6 weeks after injury. Although neuropathic pain is a common consequence after CNS injuries, little attention has been given to neuropathic pain symptoms after TBI. Magnetic resonance spectroscopy (MRS) studies in subjects with TBI show decreased brain concentrations of N-acetylaspartate (NAA), a marker of neuronal density and viability. Although decreased brain NAA has been associated with neuropathic pain associated with spinal cord injury (SCI) and diabetes, this relationship has not been examined after TBI. The primary purpose of this study was to test the hypothesis that lower NAA concentrations in brain areas involved in pain perception and modulation would be associated with greater severity of neuropathic pain symptoms. Participants with TBI underwent volumetric MRS, pain and psychosocial interviews. Cluster analysis of the Neuropathic Pain Symptom Inventory subscores resulted in two TBI subgroups: The Moderate Neuropathic Pain (n = 17; 37.8%), with significantly (p = 0.038) lower insular NAA than the Low or no Neuropathic Pain group (n = 28; 62.2%), or age- and sex-matched controls (n = 45; p < 0.001). A hierarchical linear regression analysis controlling for age, sex, and time post-TBI showed that pain severity was significantly (F = 11.0; p < 0.001) predicted by a combination of lower insular NAA/Creatine (p < 0.001), lower right insular gray matter fractional volume (p < 0.001), female sex (p = 0.005), and older age (p = 0.039). These findings suggest that neuronal dysfunction in brain areas involved in pain processing is associated with pain after TBI.

Effects of cholesterol oxidation products on exocytosis

Increase in levels of oxysterols or cholesterol oxidation products have been detected in brain areas undergoing neuroinflammation after excitotoxic injury, and the present study was carried out to elucidate possible effects of these products on exocytosis in rat pheochromocytoma-12 (PC12) cells. An increase in vesicle fusion with the cell membrane indicating exocytosis was observed by total internal reflection microscopy (TIRFM), and confirmed by capacitance measurements, after addition of 7 ketocholesterol, 24 hydroxycholesterol or cholesterol 5, 6 beta epoxide. 7 ketocholesterol induced exocytosis was attenuated by pretreatment with a disruptor of cholesterol-rich domains or "lipid rafts", methyl-beta-cyclodextrin (MbetaCD) as demonstrated by capacitance and amperometry measurements of neurotransmitter release. Moreover, treatment of cells with thapsigargin to deplete intracellular calcium, or treatment of cells with lanthanum chloride to block calcium channels resulted in attenuation of 7 ketocholesterol induced exocytosis. Fura-2 imaging showed that 7 ketocholesterol induced rapid and sustained increases in intracellular calcium concentration, and that this effect was attenuated in cells that were pre-treated with MbetaCD, thapsigargin or lanthanum chloride. Together, the results suggest that neurotransmitter release triggered by 7 ketocholesterol is dependent on the integrity of cholesterol rich lipid domains on cellular membranes and a rise in intracellular calcium, either through release from internal stores or influx via calcium channels. Increased cholesterol oxidation product concentrations in brain areas undergoing neuroinflammation may enhance exocytosis and neurotransmitter release, thereby aggravating excitotoxicity.

Mechanism of action of St John's wort in depression : what is known?

Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.

Role of acetaldehyde in the actions of ethanol on the brain — A review

Over the last 30 years, acetaldehyde has been postulated to mediate various actions of ethanol on the brain. Experiments have studied ethanol consumption after acetaldehyde infusions into the brain, in rodents with high or low activities of hepatic and brain ethanol-metabolizing enzymes, and after treatment with drugs that alter the metabolism of acetaldehyde after ethanol ingestion. Evidence that acetaldehyde is involved in the actions of ethanol has been inconsistent because of the lack of knowledge of the brain acetaldehyde concentrations required to exert their effects, the lack of correlation between the activities of ethanol-metabolizing enzymes across strains of rodents and ethanol consumption, and the lack of specificity of drugs altering acetaldehyde metabolism. The formation of significant amounts of acetaldehyde the brain in vivo after ethanol ingestion and by what mechanism has not been clearly established, although catalase is a promising candidate. Future research needs to directly demonstrate in brain the formation of acetaldehyde in vivo, determine the concentrations in brain areas involved in ethanol consumption, and evaluate the possible actions of drugs other than an ability to block acetaldehyde metabolism.

β-Endorphin concentrations in brain areas and peritoneal macrophages in rats susceptible and resistant to experimental allergic encephalomyelitis: A possible relationship between tumor necrosis factor α and opioids in the disease

Since the central nervous system and neuropeptides modulate immune functions, we investigated whether the different susceptibility of Lewis and Brown Norway rats to experimental allergic encephalomyelitis could also reflect differences in β-endorphin and substance P concentrations in brain areas and macrophages during the development of the disease. We show that β-endorphin concentrations increase much more in the hypothalamus and macrophages of Lewis rats during the development of the disease, while the increase is much lower or absent in Brown Norway rats. Tumor necrosis factor-α seems to play an important role in this difference. The administration of the opiate receptor antagonist naltrexone worsens the development of the disease, suggesting that the increase of the opioid β-endorphin might represent a mechanism to downregulate the immune response. In both strains, the concentrations of substance P do not change.

Brain distribution of radioimmunoassayable gonadotropin-releasing hormone in female goldfish: Seasonal variation and periovulatory changes

A radioimmunoassay (RIA) for [Trp 7, Leu 8]gonadotropin-releasing hormone (sGnRH) was developed to determine the gonadotropin-releasing hormone (GnRH) content in discrete brain areas of female goldfish at different stages of ovarian development. Temporal changes in serum gonadotropin (GtH) and GnRH concentrations in discrete brain areas were measured during spontaneous ovulation. There were no clear parallel changes in brain GnRH with seasonal ovarian development in goldfish. However, under a 10° temperature acclimation regimen, the GnRH content in the hypothalamus and pituitary decreased as the ovary progressed from the regressed to the mature condition; on the other hand, GnRH content in the spinal cord increased in sexually mature fish compared with that in regressed fish. Significant decreases in GnRH concentration were observed in certain brain areas (olfactory bulbs, telencephalon, hypothalamus, and pituitary) of fish undergoing spontaneous ovulation compared with those of nonovulatory fish. The simultaneous changes of GnRH concentration in these brain areas suggested that the GnRH neuronal system may function as an integrated unit for the activation of GtH secretion during ovulation in goldfish.

Chapter 9 Neuropeptide changes in aging and Alzheimer's disease

The chapter reviews the pattern of peptidergic changes in Alzheimer's disease is and compares it with changes during normal aging. Many peptides have been measured in the Alzheimer's disease brain tissue and age-matched control material. Reduced cortical levels of somatostatin (SOM) have been reported consistently, while reports of reductions in other neuropeptide systems are not consistent. Vasopressin (VP) is reported to be reduced in a number of extrahypothalamic brain regions, although statistical significance is reached only in the globus pallidus. In the cerebrospinal fluid (CSF), SOM and oxytocin (OXT) have been reported to be reduced in Alzheimer's disease. It is argued, however, that the mere determination of peptide concentrations in brain areas is not sufficient to investigate age-related or disease-related changes in peptidergic systems because the observed changes cannot be interpreted in functional terms. A different approach towards the elucidation of peptidergic changes during aging and Alzheimer's disease is the assessment of the parameters that indicate changes in cell function—that is, cell size or nucleolar size—in immunocytochemically identified peptidergic neurons. The application of such procedures to VP and OXT neurons in the human supraoptic nuclei and paraventricular nuclei has revealed increased neurosecretory activity of VP, but not of OXT cells in senescence and Alzheimer's disease.

Burn trauma induces anorexia and aberrations in CNS amine neurotransmitters.

A 30% surface area, full-thickness, open-flame burn of guinea pigs induced significant anorexia and rapid loss of body weight. Analysis of regional brain concentrations of amine neurotransmitters suggested burn-specific elevation of serotonergic neurotransmission, reduction of dopamine metabolism, and elevation of norepinephrine concentrations in brain areas thought to control feeding. These data suggest that specific regional aberrations in each of these amine neurotransmitters may contribute to the anorexia associated with major thermal injury.

Gas chromatography--mass fragmentographic determination of indole-3-acetic acid in rat brain.

Abstract— A gas chromatography‐mass fragmentographic procedure is described for the quantitation of indole‐3‐acetic acid (IAA) in rat brain. IAA was determined as its IV‐1‐pentafluoropropionyl‐methyl ester. Deuterium labeled IAA was employed as an internal standard. Assay sensitivities of at least 500 pg and 2.5 ng could be achieved by single and double ion monitoring respectively. Whole brain IAA concentrations were determined to be 11.6 + 0.75 ng/g (n = 6). IAA concentrations in brain areas ranged from 10 to 64 ng/g with highest levels in the striatum. Rat brain IAA accumulated curvilinearly with respect to time over a 90 min interval following probenecid (200 mg/kg, i.p.). The efflux of IAA from brain appears mediated in part through a probenecid‐sensitive active efflex process.

Acetycholine concentrations in brain areas of rats during three states of avoidance behavior: Normal, depression, and excitation

Acetycholine concentrations in brain areas of rats during three states of avoidance behavior: Normal, depression, and excitation