Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use.

Role of CINC-1 and CXCR2 receptors on LPS-induced fever in rats.

The classic model of fever induction is based on the administration of lipopolysaccharide (LPS) from Gram-negative bacteria in experimental animals. LPS-induced fever results in the synthesis/release of many mediators that assemble an LPS-fever cascade. We have previously demonstrated that cytokine-induced neutrophil chemoattractant (CINC)-1, a Glu-Leu-Arg (ELR) + chemokine, centrally administered to rats, induces fever and increases prostaglandin E2 in the cerebrospinal fluid. We now attempt to investigate the involvement of CINC-1 and its functional receptor CXCR2 on the fever induced by exogenous and endogenous pyrogens in rats. We also investigated the effect of reparixin, an allosteric inhibitor of CXCR1/CXCR2 receptors, on fever induced by either systemic administration of LPS or intracerebroventricular injection of CINC-1, as well as TNF-α, IL-1ß, IL-6, or ET-1, known mediators of febrile response. Our results show increased CINC-1 mRNA expression in the liver, hypothalamus, CSF, and plasma following LPS injection. Moreover, reparixin administered right before CINC-1 or LPS abolished the fever induced by CINC-1 and significantly reduced the response induced by LPS. In spite of these results, reparixin does not modify the fever induced by IL-1ß, TNF-α, and IL-6, but significantly reduces ET-1-induced fever. Therefore, it is plausible to suggest that CINC-1 might contribute to LPS-induced fever in rats by activating CXCR2 receptor on the CNS. Moreover, it can be hypothesized that CINC-1 is placed upstream TNF-α, IL-1ß, and IL-6 among the prostaglandin-dependent fever-mediator cascade and amidst the prostaglandin-independent synthesis pathway of fever.

Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood-Cerebrospinal Fluid Barrier and Blood-Brain Barrier.

Complementary and alternative medications (CAM) with known or suspected pharmacologic activity in the central nervous system (CNS) are common. These herbal preparations may cause clinically significant drug-drug interactions (DDIs) when coadministered with medications that act in the CNS. This can result in negative outcomes such as toxicity or loss of efficacy. Most drug interaction reports with CAM focus on cytochrome P450 (CYP) modulation. However, drug interactions between CAM and conventional medications may occur via mechanisms other than CYP inhibition or induction; in particular, modulation of drug transport proteins represents an important mechanism by which such interactions may occur. This article provides an updated review of transporter-mediated mechanisms by which herbal products may theoretically interact with centrally acting medications at the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. Further research is required before the true clinical impact of interactions involving modulation of centrally located membrane transporters can be fully understood.

Bromelain Degrades Aß1-42 Monomers and Soluble Aggregates: An In Vitro Study in Cerebrospinal Fluid of Alzheimer's Disease Patients.

BACKGROUND: Therapeutic approaches targeting amyloid ß42 (Aß42) oligomers may represent a promising neuroprotective strategy for the prevention and treatment of Alzheimer's disease (AD). OBJECTIVE: In this study we evaluated the ability of bromelain, a plant cysteine protease derived from pineapple stems, to interact with synthetic Aß42 monomers and oligomers. We also examined the ability of bromelain to interfere in vitro with synthetic Aß42 aggregates in the cerebrospinal fluid (CSF) of Alzheimer's disease as well as of control patients affected by other neurological diseases. METHOD: Both synthetic monomers and aggregates of Aß42 were incubated in CSF with varying concentrations of bromelain. The effects of digestion were evaluated by Western Blot analysis using the specific monoclonal antibody 4G8 to identify the patterns of residual content of Aß42. We further used rat primary cortical culture neurons (CN) to examine the cytotoxic action of this natural compound. RESULTS: We found that bromelain successfully degraded Aß42 monomers and low and high molecular weight oligomers. Indeed, when bromelain preparations of 3 and 6 mU were added to the CSF, the residual amount of Aß42 monomers and oligomers were significantly reduced when compared to the same standard Aß42 preparations incubated in CSF without bromelain. Moreover, bromelain incubations of 0.1, 0.5, and 1 mU/ml were not toxic to CN, as compared to vehicle treated cells. CONCLUSION: Overall, these results represent an important insight into the action of bromelain on Aß42 oligomers, suggesting its potential use in the therapy of AD.

Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome.

Natural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg·L(-1) for male rats and 40 mg·L(-1) for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L(-1) NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L(-1) NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier.

PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-ß-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

Impact of anesthetic agents on cerebrovascular physiology in children.

The role of the pediatric neuroanesthetist is to provide comprehensive care to children with neurologic pathologies. The cerebral physiology is influenced by the developmental stage of the child. The understanding of the effects of anesthetic agents on the physiology of cerebral vasculature in the pediatric population has significantly increased in the past decade allowing a more rationale decision making in anesthesia management. Although no single anesthetic technique can be recommended, sound knowledge of the principles of cerebral physiology and anesthetic neuropharmacology will facilitate the care of pediatric neurosurgical patients.

Pneumococcal meningitis in children: relationship of antibiotic resistance to clinical characteristics and outcomes.

BACKGROUND: The relationship of antibiotic susceptibility to clinical outcome in children with pneumococcal meningitis is uncertain. Previous studies have been limited by inclusion of relatively few patients infected with nonsusceptible pneumococci and inconsistent use of empiric vancomycin. METHODS: Medical records of 86 children with culture-confirmed pneumococcal meningitis at a single institution from October, 1991, to October, 1999, were retrospectively reviewed, and differences in presentation and outcome based on antibiotic susceptibility of pneumococcal isolates were assessed. RESULTS: Of 86 isolates 34 were nonsusceptible to penicillin (12 resistant). Of 60 isolates for which cefotaxime susceptibility data were available, 17 were nonsusceptible (12 resistant). Antibiotic susceptibility was not significantly associated with death, intensive care unit admission, mechanical ventilation, focal neurologic deficits, seizures, secondary fever, abnormal neuroimaging studies or hospital days. Children with penicillin-resistant isolates had significantly higher median blood leukocyte counts (24,100/microliter vs. 15,700/microliter, P = 0.03) and lower median CSF protein concentrations (85 mg/dl vs. 219 mg/dl, P = 0.04), were more likely to have a CSF glucose concentration of > or = 50 mg/dl (7 of 11 vs. 15 of 68, P = 0.009) and had lower rates of sensorineural hearing loss (1 of 8 vs. 25 of 40, P = 0.02) than children with isolates that were not resistant to penicillin. Children with cefotaxime-nonsusceptible isolates had an increased median duration of primary fever compared with those with nonsusceptible strains (6 days vs. 3.5 days, P = 0.02). CONCLUSIONS: In children with pneumococcal meningitis, penicillin resistance was associated with a reduced risk of hearing loss, while cefotaxime resistance was associated with a longer duration of fever. Other outcome measures were not significantly influenced by the antibiotic susceptibility of pneumococcal isolates.

Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings.

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.

Activity of LY333328 in experimental meningitis caused by a Streptococcus pneumoniae strain susceptible to penicillin.

In a rabbit model of Streptococcus pneumoniae meningitis single doses of 10 and 2.5 mg of the glycopeptide LY333328 per kg of body weight reduced bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone at 10 mg/kg/h (changes in log CFU, -0.29 +/- 0.21 and -0.26 +/- 0.22 versus -0.34 +/- 0.15/ml/h). A dose of 1 mg/kg was bacteriostatic (change in log CFU, 0.01 +/- 0.11/ml/h). In two animals receiving LY333328 at a dose of 40 mg/kg the bacterial titers were reduced by 0.54 and 0.51 log CFU/ml/h. The penetration of CSF by LY333328 was 1 to 5%. The concentrations of lipoteichoic and teichoic acids in CSF and neuronal damage were similar in ceftriaxone- and LY333328-treated animals.

Use of acetazolamide to decrease cerebrospinal fluid production in chronically ventilated patients with ventriculopleural shunts.

Acetazolamide (ACTZ), a carbonic anhydrase inhibitor, has been shown to decrease cerebrospinal fluid (CSF) production in both in vivo and in vitro animal models. We report two children with hydrocephalus who experienced multiple shunt failures, and who had externalised ventriculostomy drains (EVD) prior to ventriculopleural shunt placement. The effects of increasing doses of ACTZ on CSF production and subsequent tolerance to ventriculopleural shunts were evaluated. The patients had a 48% and a 39% decrease in their EVD CSF output when compared to baseline with maximum ACTZ dose of 75 mg/kg/day and 50 mg/kg/day, respectively (p < 0.05). This is the first report of change in CSF volume in children after extended treatment with ACTZ. ACTZ treatment in mechanically ventilated paediatric patients with hydrocephalus may improve tolerance of ventriculopleural shunts and minimise respiratory compromise. Potassium and bicarbonate supplements are required to correct metabolic disturbances.

Effects of dopamine on posttraumatic cerebral blood flow, brain edema, and cerebrospinal fluid glutamate and hypoxanthine concentrations.

OBJECTIVES: Dopamine is often used in the treatment of traumatic brain injury to maintain cerebral perfusion pressure. However, it remains unclear whether dopamine contributes to secondary brain injury caused by vasoconstriction and resulting diminished cerebral perfusion. The present study investigated the effects of dopamine in different concentrations on posttraumatic cortical cerebral blood flow (CBF), brain edema formation, and cerebrospinal fluid concentrations of glutamate and hypoxanthine. DESIGN: Randomized, placebo-controlled trial. SETTING: Animal laboratory. SUBJECTS: Eighteen male Sprague-Dawley rats subjected to a focal cortical brain injury. INTERVENTIONS: Four hours after controlled cortical impact, rats were randomized to receive physiologic saline solution (n = 6), 10-12 tig/kg/min dopamine (n = 6), or 40-50 microg/kg/min dopamine (n = 6), for 3 hrs. Cortical CBF was measured over both hemispheres by using laser-Doppler flowmetry before trauma and before, during, and after the infusion period. At 8 hrs after trauma, brains were removed to determine hemispheric swelling and water content. Cisternal cerebrospinal fluid was sampled to measure glutamate and hypoxanthine. MEASUREMENTS AND MAIN RESULTS: After trauma, cortical CBF was significantly decreased by 46% within the vicinity of the cortical contusion in all rats. Infusion of saline and 10-12 ig/kg/min dopamine did not change mean arterial blood pressure (MABP) or cortical CBF. However, infusion of 40-50 microg/kg/min dopamine, which elevated MABP from 89 to 120 mm Hg, significantly increased posttraumatic CBF within and around the contusion by 35%. Over the nontraumatized hemisphere, CBF remained unchanged. Hemispheric swelling, water content, cerebrospinal fluid glutamate, and hypoxanthine levels were not affected by dopamine in the given dosages. CONCLUSIONS: Under the present study design, there was no evidence for a dopamine-mediated vasoconstriction, because posttraumatic cortical CBF was increased by dopamine-induced elevation of MABP. However, the increase in CBF did not significantly affect edema formation or cerebrospinal fluid glutamate and hypoxanthine levels.

The effect of intravenous gadolinium on the magnetic resonance appearance of cerebrospinal fluid.

The authors determined whether a sufficient amount of intravenously administered gadolinium enters the cerebrospinal fluid (CSF) to visibly shorten the T1 relaxation time. Transfer of intravenously administered contrast media into the CSF has been previously documented for iodinated contrast materials; however, the change in computed tomography density is not sufficient to have a clinically useful myelographic effect. Visible shortening of the T1 of CSF on gadolinium-enhanced magnetic resonance imaging of the spine may have clinical use. Twelve dogs were given gadolinium, and CSF was sampled at intervals over a 6-hour period. The T1 values of the CSF samples were quantitated and plotted against time. The average decrease in T1 was 23% at 60 minutes, which is nearly the peak effect. The increased signal intensity was visible at clinical window settings at 60 minutes. It is possible that this may be clinically useful for certain types of examinations. Importantly, this should be recognized as a normal appearance, and not necessarily a sign of pathology.

Cervical myelography in dogs using iohexol.

Iohexol, a non-ionic water-soluble radiographic contrast medium, was used for cervical myelography in dogs (10-17 kg). The animals remained clinically normal following myelography, with no evidence of seizures. At 10 days after myelography there was a slight, but significant (p less than 0.05) increase in neutrophils in the cerebrospinal fluid; these cell numbers had returned to normal by the time of necropsy at 60 days after myelography. This investigation suggests that iohexol may be suitable for clinical myelography in the dog.

The influence of myoneural blockers on intracranial dynamics.

A series of animals was studied to evaluate the effect of commonly used myoneural blockers (curare, succinylcholine, gallamine, and pancuronium) on intracranial physical dynamics. Of this group, only curare alters intracranial pressure. Histamine release secondary to curare administration results in bronchoconstriction with subsequent major alterations in pulmonary ventilation. Resultant hypercarbia along with a decreased cerebral vascular resistance affects intracranial dynamics by alterations in cerebral blood flow; changes in CSF flow patterns passively reflect the alterations in intracranial pressure. These changes can be blocked by prior treatment with antihistamines.