The rupture of an aneurysm in subarachnoid hemorrhage (SAH) is a dramatic event causing a severe impact on the brain and a transient or permanent ischemic condition. Several types of responses to meet the challenges of SAH have been found in the acute phase, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, elevated levels of brain natriuretic peptide (BNP), and disturbances in cerebral and systemic metabolism. Cerebral metabolism and the endocrine stress response in the ultra-early phase was investigated in a novel porcine model of SAH in which autologous blood was injected to the anterior skull base. Early activation of the HPA axis was found with rapid elevation of adrenocorticotrophic hormone, cortisol and aldosterone. The peak values of these hormones were early and may be impossible to catch in patients. There were indications of a sympathetic nervous response with excretion of catecholamines in urine as well as plasma chromogranin-A elevation. Cerebral microdialysis suggested immediate substrate failure followed by hypermetabolism of glucose. The animal model seems suited for further studies of aneurysmal SAH. NT-proBNP was investigated in 156 patients with SAH, there was a dynamic course with increasing levels during the first 4 days of the disease. Factors predicting high NT-proBNP load included female sex, high age, high Troponin-I at admission, angiographic finding of an aneurysm and worse clinical condition at admission. High levels of NT-proBNP were correlated to factors indicating a more severe disease, suggesting the initial injury in aneurysmal SAH is an important factor in predicting high NT-proBNP during the acute stage of the disease. Measurements with indirect calorimetry were performed daily during the first week after SAH on 32 patients with SAH. There was a dynamic course with increasing energy expenditure (EE) the first week after SAH. Comparisons with three predictive equations indicated that measured EE generally is higher than predicted, but considerable variation exists within and between patients, indicating that prediction of EE in SAH is difficult. Altogether, the studies demonstrate a complicated response in acute SAH that needs to be further studied to increase possibility of good outcome in SAH patients.

The objective of this study was to investigate the role of organic cation transporters (OCTs) in the uptake of hydrophilic drugs into the olfactory bulb and subsequently to the brain. Two OCT2 substrates, amantadine and cimetidine were used as model drugs for this purpose. Bovine nasal explants (olfactory and respiratory tissue) were used as an in vitro model for preliminary screening to identify the role of transporters involved in the uptake of drug across these tissues. It was observed from both PCR and immunohistochemistry that OCTs, OCT2, OCTN1 and OCTN2 were present in the bovine respiratory and olfactory mucosa. Transport studies of amantadine in the presence and absence of OCT2 and OCTN2 inhibitors indicated that both these transporters play a role in the transport of amantadine across the bovine respiratory mucosa, whereas transport across the olfactory mucosa was predominantly via OCT2. This was followed by in vivo studies in rats where the blood, striatum and olfactory bulb concentrations of amantadine were determined following intranasal and intra-arterial administration. Shortly after nasal administration, the olfactory bulb concentrations exceeded the concentrations in the striatum suggesting the olfactory pathway to be the major route of uptake. Co-administration of the drug with an OCT2 inhibitor intranasally showed statistically significant reductions in the brain uptake of amantadine. A synergistic inhibitory effect on amantadine uptake was observed with the combined inhibition OCT2 and OCTN2. Additionally, the CNS exposure of these drugs following intranasal administration in the presence and absence of the OCT inhibitors was evaluated using the ratio of the free drug concentrations in the brain compared to plasma. While the plasma concentration profiles were similar both in the presence and absence of inhibition, the free drug ratios were highest when no inhibitor was included. Additionally similiar in vivo studies were also carried out for a second model drug, cimetidine, where cimetidine uptake into the rat brain was found to be significantly reduced in the presence of the OCT2 inhibitor, pentamidine. This demonstrates that there was a greater CNS exposure to each drug when OCT transporters were active, confirming their role in their direct CNS distribution from the nasal cavity to the brain. The results of this study suggest that OCT substrates might be good candidates for the delivery to the brain via the olfactory route.

<div>As the soft tissue that transmits muscular forces to the bony skeleton, tendons play a key role in the human musculoskeletal system and must adapt over time to repeated mechanical loads to maintain functionality. Resistance exercise is one of the primary stimuli for increases in tendon size and strength in healthy, young individuals, but similar benefits are not observed in healthy, aged tendon. This failure in the elderly to adapt, along with the fact that tendons inevitably decline in morphology and function with age, puts older individuals at an increased risk of poor tendon health, subsequent injury, and a compromised quality of life. Alternative strategies to preserve and strengthen aged tendon has gone largely unexplored, highlighting a critical need to determine an effective stimulus for tendon adaptations in aging populations</div><div>The purpose of this study was to determine if age impacts the delivery of orally-consumed amino acids (AA) to the peritendinous Achilles space. If so, this investigation could serve as the foundation for future studies to evaluate the efficacy of supplemental amino acids for inducing positive adaptations in tendon during exercise. Furthermore, an enzyme-linked immunosorbent assay (ELISA) was performed to quantitively measure procollagen, a precursor of collagen, in the samples to evaluate the impact on supplemental amino acids on collagen synthesis. </div><div>To assess amino acid delivery, a microdialysis fiber was inserted into the peritendinous space anterior to the Achilles tendon in healthy young (n = 7, 21-30 years) and elderly (n = 6, 60-75 years) men and women after a twelve-hour fast. After baseline collection, subjects consumed a non-caloric, noncaffeinated AA beverage (16.65 g). Microdialysis samples were collected every fifteen minutes for four hours and analyzed using reverse-phase high-performance liquid chromatography. </div><div>Amino acid delivery to the peritendinous space was not compromised with age, and the administration of amino acids upregulated procollagen synthesis significantly more in healthy, elderly subjects than in those that are healthy and young. Though preliminary, these findings provide a strong foundation for future studies assessing the impact of amino acid supplementation as novel impetus for tendon adaptations in the elderly. </div><div><br></div>

It is well established that low level Pb-exposure is associated with a wide range of cognitive and neurobehavioral dysfunctions in children. In fact, Pb-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum - the anatomical sites which are crucial in modulating emotional response, memory and learning. Previously it was also shown that nitric oxide (NO) signaling pathway as well as glutamatergic neurotransmission are both involved in brain development, neurotoxicity and neurodegeneration processes whereas Pb2+ interfere with both. For this reason we investigated the effect of ontogenetic Pb2+ exposure on dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) of rats after amphetamine (AMPH) and/or 7-nitroindazole (7-NI) administration. Furthermore, the possible role of oxidative stress in Pb2+-induced neurotoxicity in prenatally Pb2+-treated rats was explored in the content of hydroxyl radical (HO•) species in mPFC after AMPH and/or 7-NI injection, assessed by HPLC analysis of 2.3-dihydroxybenzoic acid (2.3-DHBA) - spin trap product of salicylate. As shown, the results of this study suggest that Pb2+ exposure during intrauterine life did not substantially affect cortical dopaminergic neurotransmission in adult offspring rats evaluated by means of microdialysis of mPFC and the content of the cortical HO•. It is likely that striatum, nucleus accumbens or other dopamine rich brain areas are more intricately associated with Pb2+ precipitated behavioral, dopamine - dependent impairments observed in mammalians.

In the neonatally 6-hydroxydopamine (6-OHDA)-lesioned rat hyperlocomotor activity, first described in the 1970s, was subsequently found to be increased by an additional lesion with 5,7-dihydroxytryptamine (5,7-DHT) (i.c.v.) in adulthood. The latter animal model (i.e., 134 μg 6-OHDA at 3 d postbirth plus 75 μg 5,7-DHT at 10 weeks; desipramine pretreatments) was used in this study, in an attempt to attribute hyperlocomotor attenuation by D,L-amphet-amine sulfate (AMPH) and m-chlorophenylpi-perazine di HCl (mCPP), to specific changes in extraneuronal (i.e., in vivo microdialysate) levels of dopamine (DA) and/or serotonin (5-HT). Despite the 98-99% reduction in striatal tissue content of DA, the baseline striatal microdialysate level of DA was reduced by 50% or less at 14 weeks, versus the intact control group. When challenged with AMPH (0.5 mg/kg), the microdialysate level of DA went either unchanged or was slightly reduced over the next 180 min (i.e., 20 min sampling), while in the vehicle group and 5,7-DHT (alone) lesioned group, the microdialysate level was maximally elevated by ∼225% and ∼450%, respectively - and over a span of nearly 2 h. Acute challenge with mCPP (1 mg/kg salt form) had little effect on microdialysate levels of DA, DOPAC and 5-HT. Moreover, there was no consistent change in the microdialysate levels of DA, DOPAC, and 5-HT between intact, 5-HT-lesioned rats, and DA-lesioned rats which might reasonably account for an attenuation of hyperlocomotor activity. These findings indicate that there are other important neurochemical changes produced by AMPH-and mCPP-attenuated hyperlocomotor activity, or perhaps a different brain region or multiple brain regional effects are involved in AMPH and mCPP behavioral actions.

5-HT2A/2C receptors are one of the most important in controlling basal ganglia outputs. In rodent models of Parkinson's disease (PD) blockade of these receptors increases locomotion and enhances the actions of dopamine (DA) replacement therapy. Moreover, previously we established that 5-HT 2A/2C antagonist attenuate DA D1 agonist mediated vacuous chewing movements (VCMs) which are considered as an animal representation of human dyskinesia. These findings implicate 5-HT neuronal phenotypes in basal ganglia pathology, and promote 5-HT2 antagonists as a rational treatment approach for dyskinesia that is prominent in most instances of PD replacement therapy. In the current study we determined whether ketanserin (KET) and/or amphetamine (AMPH) affected dopaminergic neurotranssmision in intact and fully DA-denervated rats. Moreover, we looked into extraneuronal content of HO. of the neostriatum after AMPH and/or KET injection, assessed by HPLC analysis of dihydroxybenzoic acids (2,3- and 2, 5-DHBA) - spin trap products of salicylate. Findings from the present study demonstrated that there are no substantial differences in extraneuronal HO. generation in the neostriatum between control and parkinsonian rats. KET did not affect DA release in the fully DA-denervated rat's neostriatum and also did not enhance HO. production. As 5-HT2A/2C receptor-mediated transmission might prove usefulness not only in addressing motor complications of PD patients (dyskinesia) but also in addressing non-motor problems such depression and/or L-DOPA evoked psychosis, the findings from the current study showed that the use of 5-HT2A/2C receptor antagonists in Parkinson's disease does not impend the neostriatal neuropil to be damaged by these drugs. We concluded that 5-HT2A/2C receptor antagonists may provide an attractive non-dopaminergic target for improving therapies for some basal ganglia disorders.

To explore interactive deleterious effects of the teratogens ethanol and cadmium, pregnant rats were given cadmium (CdCl2, 50 ppm) and/or ethanol (10%), or tap water (controls) in the drinking water for the entire 21 days of pregnancy. At 3 months after birth, in vivo microdialysis was used to determine that there was a 4000% evoked release of DA by AMPH (AMPH, 4.0 mg/kg i.p.) in the striatum of rats exposed prenatally to both ethanol and cadmium, vs. a 2000% evoked release by AMPH in rats exposed prenatally to only ethanol or cadmium or tap water. Haloperidol (HAL)-evoked DA release was suppressed in groups exposed prenatally to ethanol, while HAL-evoked DOPAC and HVA release was greatest after co-exposure to prenatal cadmium and ethanol. These in vivo microdialysis results indicate that ontogenetic co-exposure to cadmium, and ethanol produces a long-lived suppressive effect on HAL-evoked DA release and a long-lived enhancing effect on AMPH-evoked DA release in rat striatum. These findings clearly demonstrate that there is marked alteration in dopaminergic regulation after ontogenetic cadmium and ethanol co-exposure, which in this regard resembles the reaction of the striatonigral pathway on AMPH-evoked DA release in rats with behavioral sensitization.

The intracellular second messenger nitric oxide (NO) is implicated in a variety of physiological functions, including release and uptake of dopamine (DA). In the described study, in vivo microdialysis and differential pulse voltammetric techniques were used to determine the involvement of NO in release of DA and its metabolites (dihydroxyphenylalanine, DOPAC; homovanillic acid, HVA) in neostriatum of freely moving rats. While the NO donor molsidomine (30.0 mg/kg; MOLS) and neuronal NO synthase- (nNOS-) inhbitor 7-nitroindazole (10.0 mg/kg; 7-NI) had no effect on the basal in vivo microdialysate level of DA, 7-NI specifically enhanced D,L-amphetamine- (1.0 mg/kg i.p.; AMPH) evoked release of DA. Basal or AMPH effects on DOPAC and HVA levels were not influenced by MOLS or 7-NI. Findings indicate that nitrergic systems have an important role in mediating effects of AMPH on dopaminergic systems.

No description available.

The role of chemokines in immune function is clearly established. Recent evidence suggests that these molecules also play an important role in the CNS as modulators of neuronal activity. The chemokine CXCL12 has been identified in several regions of the adult rat brain including the substantia nigra, ventral tegmental area and caudate putamen. CXCR4, a receptor activated by CXCL12, is expressed by dopaminergic neurons in the substantia nigra. The research presented herein explored the behavioral modulation of CXCL12, expression of the CXCR4 receptor in the forebrain of the adult rat and the effect of CXCL12 administration on extracellular dopamine and glutamate release in the medial shell of the nucleus accumbens. This research furthered our understanding of how CXCL12 can affect behavior and suggested that the modulation of cocaine-induced behavior by CXCL12 is due to an interaction with CXCR4 receptors in the mesolimbic and nigrostriatal dopamine pathways. The data presented tested the effects of intracranial injections of CXCL12 on cocaineinduced locomotion and stereotypic activity in adult male Sprague Dawley rats. Results demonstrate that intracerebroventricular administration of CXCL12 (25 ng/4 μl) 15 minutes prior to cocaine (20 mg/kg IP) produced a significant potentiation of both ambulatory and stereotypic activity as compared to cocaine alone. The effects of CXCL12 were blocked by administration of the selective CXCR4 antagonist, AMD 3100. Administration of CXCL12 into specific brain regions was performed to further understand the site of action of CXCL12. Bilateral administration of CXCL12 (25 ng/0.5 μl) into the ventral tegmental area 15 minutes prior to cocaine (20 mg/kg IP) significantly potentiated cocaine-induced ambulatory activity, whereas microinjections of CXCL12 into the caudate putamen selectively increased stereotypy. Conversely, administration of CXCL12 into the lateral shell of the nucleus accumbens resulted in an inhibition of cocaine-stimulated ambulatory activity. No alterations in ambulatory or stereotypic activity were observed following CXCL12 administration into the core of the nucleus accumbens. Immunohistochemistry results showed evidence of CXCR4 within the caudate putamen and lateral shell of the nucleus accumbens. Dual labeling immunofluorescence demonstrated that CXCR4 is co-expressed on cholinergic and GABAergic neurons, including co-localization with the D1 dopamine receptor in both the caudate putamen and lateral shell of the nucleus accumbens. Results demonstrated that CXCR4 is co-expressed with choline acetyl transferase, a marker for cholinergic neurons, with GAD C38, a marker for GABAergic neurons, and with the D1 dopamine receptor, also a marker for GABAergic medium spiny neurons. High pressure liquid chromatography studies were conducted using brain dialysate collected from microdialysis probes surgically implanted in the medial shell of the nucleus accumbens. Results demonstrated no significant change in extracellular dopamine or glutamate following an acute administration of CXCL12. The research presented herein sought to determine the behavioral modifications of CXCL12 as well as the localization of CXCR4 in the forebrain of the adult rat. This research also examined changes in extracellular dopamine and glutamate levels following CXCL12 administration. Results demonstrated that CXCL12 does alter the behavioral activity of cocaine. Results also showed that CXCR4 is localized on cholinergic and GABAergic neurons that could be contributing to the behavioral modification. These results have extended our understanding of the complex mechanisms of CXCL12 and CXCR4 in the mesolimbic and nigrostriatal dopamine pathways of the adult rat brain. / Pharmacology