Central Nervous System Mechanisms Research Articles

Multiple symptoms of higher brain dysfunction caused by Marchiafava–Bignami disease in a patient with dermatomyositis

A 65-year-old woman with dermatomyositis (DM) was admitted because of disorientation, mental dysfunction, and disturbance of consciousness. Prior to admission, she suffered from septic and hypovolemic shock. There was no evidence of active DM on physical examination and laboratory tests. Cerebrospinal fluid examination revealed no signs of meningitis. Because of clinical symptoms and findings on magnetic resonance images, such as the lesion in the splenium of the corpus callosum that was a low-intensity area on T1-weighted images and a high intensity on T2-weighted images; she was diagnosed as Marchiafava-Bignami disease (MBD). She received a combination of vitamin B, vitamin E, vitamin C, and nicotinic acid. Her symptoms improved gradually, and she was discharged at 1.5 months after admission. There has been no report of a case of DM with MBD. This report may provide useful data with regard to the mechanisms of central nervous system (CNS) disorders in patients with DM.

The importance of altered gene promoter methylation and transcription factor binding in developmental programming of central appetitive drive

The importance of altered gene promoter methylation and transcription factor binding in developmental programming of central appetitive drive

Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans

Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22+/-1 years; body mass index, 23+/-1 kg/m2; values are means+/-S.E.M.) received a 4-h intravenous infusion of 20% Intralipid or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and Q (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2+/-1.0 and +2.4+/-1.2 beats/min), systolic BP (+14.0+/-1.6 and +3.2+/-2.5 mmHg) and diastolic BP (+8.2+/-1.0 and -0.1+/-1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid compared with placebo (P<0.001). The change in BP with Intralipid resulted from an increase in SVR (Q/mean arterial pressure; P<0.001) compared with baseline, without a change in Q. MSNA burst frequency increased during Intralipid infusion compared with baseline (+4.9+/-1.3 bursts/min; P<0.05), and total MSNA (frequencyxamplitude) was augmented 65% (P<0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F2-isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs.

Effects of occupational microwave irradiation on heat shock protein 70 expressions in rat hippocampus

To study the change of heat shock protein (HSP)70 expression after exposure to occupational microwave in rats hippocampus, and explore the role of HSP70 in the mechanism of bio-effect of microwave irradiation. The animal model was established by whole body exposures in 90, 5 W/cm(2) microwave irradiation field for 20 min in rats. Changes of the mRNA of hsp70 expressions in rat hippocampus at different time were studied by RT-PCR, and the protein change by Western blot. The mRNA and protein expression of hsp70 in rat hippocampus increased after 90 W/cm(2) and 5 W/cm(2) microwave irradiation for 20 min. The anal temperature and the value of SAR increased significantly. These changes were positively correlated with power and irradiation time of microwave. The results indicated that microwave irradiation led to HSP70 syntheses effectively. Microwave irradiation can obviously induce the thermal effect and activate HSP70, and initiate the endogenous protective mechanism of central nervous system.

On the Central Mechanism Underlying Ghrelin’s Chronic Pro‐Obesity Effects in Rats: New Insights from Studies Exploiting a Potent Ghrelin Receptor Antagonist

In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

Pharmacological Treatment for Heart Failure: A View From the Brain

Systolic heart failure is a feed-forward phenomenon with devastating consequences. Impaired cardiac function is the initiating event, but central nervous system mechanisms activated by persistent altered neural and humoral signals from the periphery play an important sustaining role. Animals with experimentally induced heart failure have neurochemical abnormalities in the brain that, when manipulated, profoundly affect sympathetic drive, volume regulation, and cardiac remodeling--critical determinants of outcome. This brief review explores recent studies that provide a strong rationale for the development of pharmaceutical agents that target central nervous system abnormalities in heart failure.

On the central mechanism underlying ghrelin’s chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor (GHS-R1A) antagonist.

In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

Effect of Tianeptine on Glucose Tolerance with Insulin Secretion in Human: Potential Anti-Diabetic Effect of the Drug

Due to the fact that drugs which interfere with the serotonin (5-HT) uptake (doxepin, sertraline, fluvoxamine and fluoxetine), were able to minimize the insulin release from islet beta-cells and counteract hypoglycemia, we investigated the effects of tianeptine, a drug which enhances 5-HT uptake during the oral glucose tolerance test. We found that the drug triggered significant and sustained insulin rises which were opposite to the plasma glucose decreases. The fact that significant noradrenaline/adrenaline (NA/Ad) plasma ratio paralleled insulin rises throughout the test is consistent with the excitatory role played by the peripheral neural sympathetic activity. Additionally, the positive correlations registered between NA versus DA (dopamine) plasma levels indicate that the latter arose from sympathetic nerves rather than the adrenal glands. Furthermore, the significant reductions of both platelet and plasma 5-HT registered throughout the OGTT plus tianeptine test support the postulation that reduction of the parasympathetic drives is occurring. This parasympathetic drive is responsible for the secretion of 5-HT from the enterochromaffin cells. Finally, considering that circulating 5-HT excites alpha-cells and modulates beta-cells, it is possible to infer that minimization of this factor contributed to the insulinogenic effect displayed by the association of this drug to an oral glucose load. We also discussed the peripheral and central nervous system mechanisms responsible for the insulinogenic effect registered throughout the test.

Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain

Over the years, many have viewed Fibromyalgia syndrome (FMS) as a so-called “functional disorder” and patients have experienced a concomitant lack of interest and legitimacy from the medical profession. The symptoms have not been explained by peripheral mechanisms alone nor by specific central nervous system mechanisms. In this study, we objectively evaluated the cerebral response to individually calibrated pain provocations of a pain-free body region (thumbnail). The study comprised 16 female FMS patients and 16 individually age-matched controls. Brain activity was measured using functional magnetic resonance imaging (fMRI) during individually calibrated painful pressures representing 50mm on a visual analogue scale (VAS) ranging from 0 to 100mm. Patients exhibited higher sensitivity to pain provocation than controls as they required less pressure to evoke equal pain magnitudes (UA=48, p<.002). Despite lower pressures applied in patients at VAS 50mm, the fMRI-analysis revealed no difference in activity in brain regions relating to attention and affect or regions with sensory projections from the stimulated body area. However, in the primary link in the descending pain regulating system (the rostral anterior cingulate cortex) the patients failed to respond to pain provocation. The attenuated response to pain in this brain region is the first demonstration of a specific brain region where the impairment of pain inhibition in FMS patients is expressed. These results validate previous reports of dysfunctional endogenous pain inhibition in FMS and advance the understanding of the central pathophysiologic mechanisms, providing a new direction for the development of successful treatments in FMS.

β 1-Adrenoceptor distribution in the rat brain: An immunohistochemical study

Current knowledge of the central nervous system distribution of the β 1-adrenergic receptors (β 1-AR) is incomplete. Here we present a general map of the β 1-AR distribution in the rat brain. β 1-AR-immunoreactivity was detected throughout the entire rat brain, but particularly dense staining was observed in the cerebellar cortex and basal ganglia. Brainstem areas displaying significant β 1-AR-immunoreactivity include the ventrolateral medulla, nucleus ambiguus and the nucleus of the solitary tract. Within the hypothalamus, only the paraventricular nucleus and the median eminence (ME) showed β 1-AR immunostaining. Numerous β 1-AR-immunoreactive cells were also found in the hippocampus, basal ganglia and cerebral cortex. These results extend our knowledge of the expression profile of β 1-AR in the central nervous system. The identification of several distinct β 1-AR immunoreactive substrates linked with neuropathophysiological roles in cardiovascular disease supports the hypothesis that the therapeutic benefit of β 1-AR blockade may be conferred at least in part through central nervous system mechanisms.

Laryngeal constriction during hypoxic gasping and its role in improving autoresuscitation in two mouse strains

Laryngeal closure following hypoxic gasps has been documented, but its efficacy in improving autoresuscitation capacity is unknown. We studied SWR/J mice who normally cannot autoresuscitate and the C57/BLJ strain who can. We evaluated the effects of elevated end-inspiratory lung volume immediately following a gasp. We compared upper airway-intact mice with tracheostomized mice in which the vocal cords are bypassed. We used the techniques of repeated autoresuscitate trials to test autoresuscitation capability. Both SWR/J and C57/BLJ mice could maintain elevated lung volume immediately after a gasp (breath holding). Such breath holding increased autoresuscitation ability in C57/BLJ mice but did not in SWR/J mice. In SWR/J mice, the duration of the breath holds was less than that in the C57/BLJ mice. These findings indicate that gasp-associated breath holding improves autoresuscitation capability during repeated autoresuscitation trials. Also, they show that SWR/J mice have a deficiency in central nervous system mechanisms regulating glottic closure during hypoxic gasping.

Endogenous cortisol suppression with metyrapone enhances acoustic startle in healthy subjects

Previous human studies have shown that excess cortisol sufficient to fully occupy central nervous system (CNS) corticosteroid receptors may reduce startle eye blink. The present study tested whether cortisol depletion and the resulting reduction in activity of CNS corticosteroid receptors has the opposite effect. In a single-blind, placebo-controlled, randomized study, eye blink EMG responses to 105 dB acoustic startle stimuli were assessed in 25 healthy subjects who received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. As expected, metyrapone significantly reduced salivary cortisol, indicating effective endogenous cortisol suppression. Startle eye blink responses were significantly increased in the metyrapone group. Short-term habituation of the startle reflex was not different between groups. Our results suggest that startle is enhanced during depletion of cortisol. This effect may be mediated by CNS mechanisms controlling cortisol feedback.

Upregulation of water channel aquaporin-4 in experimental autoimmune encephalomyeritis

Aquaporin-4 (AQP4) is a water channel protein that plays an important role in water movement in the central nervous system (CNS). Recently, presence of anti-AQP4 antibody has been reported in the sera from patients with neuromyelitis optica. AQP4 is therefore a possible target for inflammatory mechanisms in CNS. In the present investigation, we performed semi-quantitative analysis of AQP4-mRNA in brain and spinal cord from mice affected with experimental autoimmune encephalomyelitis (EAE) using real-time PCR. AQP4-mRNA expression was increased in EAE; reaching a peak in the spinal cord at 14 days, and in the brain at 21 days after first inoculation. Immunohistochemical analysis showed that AQP4 is expressed on astrocytes, indicating that the increase in AQP4 expression may correlate with astrocytic activation. This is the first study to demonstrate upregulation of AQP4 in EAE. The upregulation of AQP4 could be involved in the development of inflammation in the acute phase of EAE.

Mechanisms for the Regulation of State Changes in the Central Nervous System

Current work on central nervous system (CNS) mechanisms underlying behavior has expanded from consideration of specific sensory codes or motor controls to the analyses of global CNS states. These include states of arousal, alertness, attention, emotional states regarding emotion and motivation, and states of addiction, which carry great importance for medicine and public health. In this brief introduction, orderly neuroanatomical concepts of forebrain pathways regulating motivated behaviors are presented. Neuropeptides often coordinate large sets of responses associated with an individual behavioral state. Here, we emphasize some of the central roles for opioid peptides. We also mention a few outstanding unanswered questions related to this area of neuroscience.

Effects of Acamprosate on Neuronal Receptors and Ion Channels Expressed in Xenopus Oocytes

Acamprosate (calcium acetylhomotaurinate) has proven to be a moderately effective pharmacological adjunct for the treatment of alcoholism. However, the central nervous system mechanism by which acamprosate reduces alcohol relapse remains unclear. Here we survey a number of metabotropic receptors, ligand-gated ion channels, and voltage-gated ion channels, to determine if acamprosate has actions at these sites in the central nervous system. Xenopus oocytes were injected with cDNAs or cRNAs encoding metabotropic glutamate receptors 1 and 5, M1 muscarinic receptors, glycine alpha1 homomeric and alpha1beta1 heteromeric receptors, gamma-aminobutyric acid A (GABA(A)alpha4beta3delta, alpha4beta3gamma2s, and alpha1beta2gamma2s) receptors, vanilloid receptor 1, and various combinations of alpha and beta subunits of voltage-gated Na+ channels. Electrophysiological responses were measured using two-electrode voltage clamp parameters after activation with agonists or voltage steps (for the voltage-gated channels). Acamprosate (0.1 to 100 microM) was pre-applied for 1 minute, followed by co-application with agonist. Acamprosate was also applied with ethanol to determine if it altered ethanol responses at some of these receptors and channels. None of the receptors or ion channels responded to acamprosate alone. Acamprosate also failed to alter the activation of receptors or channels by agonists or after activation of voltage-gated channels. There was no effect of acamprosate on ethanol responses at GABA(A)alpha1beta2gamma2s receptors or Na+ channels. Acamprosate does not significantly modulate the function of these receptors and ion channels at clinically relevant concentrations. Thus, the clinical effectiveness of acamprosate in the treatment of alcoholism is not likely due to direct effects on these receptors or ion channels.

Estradiol regulates alternative splicing of estrogen receptor-α mRNA in differentiated NG108-15 neuronal cells

The biological actions of estrogen are mostly conveyed through interaction with two different types of estrogen receptor (ER), ER-α and ER-β. With regard to ER-α, an alternatively spliced form and its translated product, truncated estrogen receptor product-1 (TERP-1), have been identified in the rat pituitary. TERP-1 has the ability to inhibit the ER binding to DNA response element by forming hetero-dimers with the wild-type ER. Furthermore, TERP-1 expression increased concurrently with serum estrogen levels. Although estrogen also plays important roles in the central nervous system, the existence and regulatory mechanism of alternatively spliced ER-α mRNA expression has remained unclear. The present study evaluated the expression of the alternatively spliced form of the ER-α gene, and examined the influence of a representative ER ligand, 17β-estradiol (E 2), on the expression in differentiated NG108-15 neuronal cells. A real-time RT-PCR analysis using primer sets designed to amplify from exons 3 to 4, exons 4 to 5, exons 5 to 6, exons 6 to 7, and exons 7 to 8 of the mouse ER-α gene revealed the existence of alternatively spliced ER-α mRNA and its putative transcription initiation site, located between exon 4 and exon 5. Although E 2 had no apparent effect on the overall expression of ER-α mRNA, it reduced the incidence of the alternatively spliced form of ER-α. The down-regulation by E 2 predominantly arose via binding to nuclear ERs. The present study demonstrated that alternatively spliced ER-α mRNA is expressed in differentiated NG108-15 neuronal cells, and provides evidence for the functional up-regulation of ER-α via the ligand-binding activation of ERs.

Pituitary and/or Peripheral Estrogen-Receptor α Regulates Follicle-Stimulating Hormone Secretion, Whereas Central Estrogenic Pathways Direct Growth Hormone and Prolactin Secretion in Postmenopausal Women

Estradiol (E(2)) stimulates GH and prolactin secretion and suppresses FSH secretion in postmenopausal women. Whether central nervous system (CNS) or pituitary mechanisms (or both) mediate such actions is not known. Our objective was to distinguish between hypothalamic and pituitary or peripheral (hepatic) actions of E2. This study was performed in an academic medical center. This was a double-blind, prospectively randomized, placebo (Pl)-controlled study. The capability of a selective, noncompetitive, non-CNS permeant estrogen receptor (ER)-alpha antagonist, fulvestrant (FUL) to antagonize the effects of transdermal E2 and Pl on GH, prolactin, and FSH secretion was assessed in 43 women (ages 50-80 yr) in a four parallel-cohort study. Each woman received four secretagogue infusions to stimulate GH secretion. IGF-I and its binding proteins were measured secondarily. Administration of Pl/E2 increased GH and prolactin concentrations by 100%, and suppressed FSH concentrations by more than 50% (each P<or=0.004 compared with Pl/Pl). Treatment with FUL/E2 compared with Pl/E2 partially relieved estrogen's inhibition of FSH secretion (P=0.041), without altering E2's stimulation of prolactin secretion. ANOVA further revealed that: 1) estrogen milieu (P=0.014) and secretagogue type (P<0.001) each determined GH concentrations; 2) FUL/Pl suppressed IGF-I concentrations (P<0.001); 3) FUL abrogated estrogen's elevation of IGF binding protein-1 concentrations (P<0.001); and 4) FUL did not oppose estrogen's suppression of IGF binding protein-3 concentrations (P<0.001). Responses to a non-CNS permeant ERalpha antagonist indicate that E2 inhibits FSH secretion in part via pituitary/peripheral ERalpha, drives prolactin output via nonpituitary/nonperipheral-ERalpha effects, and directs GH secretion and IGF-I-binding proteins by complex mechanisms.

Psychiatric Medications for the Treatment of Pruritus

To review the use of psychiatric medications in the treatment of pruritus. A literature review was conducted using the key words pruritus, psychiatric, and treatment. Three categories of pruritus are described: dermatologic, systemic, and psychogenic. Peripheral and central nervous system mechanisms of pruritus are reviewed. Conventional dermatologic treatments for pruritus are contrasted with some of the common psychopharmacologic treatment modalities that include anxiolytic, antidepressant, and antipsychotic agents. A treatment algorithm is offered to help guide the treatment of patients with pruritus. Psychiatric medications have been used successfully in the treatment of pruritus that is associated with both psychocutaneous and systemic disorders, which are resistant to conventional treatment.

Cannabidiol potentiates pharmacological effects of Δ 9-tetrahydrocannabinol via CB 1 receptor-dependent mechanism

Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Δ 9-tetrahydrocannabinol (Δ 9-THC). However, such interactions have not sufficiently been clear and may have important implications for understanding the pharmacological effects of marijuana. In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Δ 9-THC on locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory in the eight-arm radial maze task in mice. In addition, we measured expression level of cannabinoid CB 1 receptor at striatum, cortex, hippocampus and hypothalamus. Δ 9-THC (1, 3, 6 and 10 mg/kg) induced hypoactivity, catalepsy-like immobilisation and hypothermia in a dose-dependent manner. In addition, Δ 9-THC (1, 3 and 6 mg/kg) dose-dependently impaired spatial memory in eight-arm radial maze. On the other hand, cannabidiol (1, 3, 10, 25 and 50 mg/kg) did not affect locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory on its own. However, higher dose of cannabidiol (10 or 50 mg/kg) exacerbated pharmacological effects of lower dose of Δ 9-THC, such as hypoactivity, hypothermia and impairment of spatial memory. Moreover, cannabidiol (50 mg/kg) with Δ 9-THC (1 mg/kg) enhanced the expression level of CB 1 receptor expression in hippocampus and hypothalamus. Cannabidiol potentiated pharmacological effects of Δ 9-THC via CB 1 receptor-dependent mechanism. These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.

Differing Pattern of Sympathoexcitation in Normal-Weight and Obesity-Related Hypertension

Hypertension in normal-weight and obese individuals is characterized by activation of the sympathetic nervous system. Measurement of spillover of the sympathetic transmitter, norepinephrine, to plasma indicates that the regional pattern of sympathetic activation in the 2 "variants" of essential hypertension differs, excluding the heart in obesity-related hypertension. Whether sympathetic nerve firing characteristics also differ is unknown. We studied multiunit and single fiber sympathetic nerve firing properties in patients with normal-weight hypertension and obesity-related hypertension, comparing these with nerve characteristics in normal-weight and obese people with normal blood pressure. Both normal-weight hypertensive (n=10) and obese hypertensive (n=14) patients had increased total multiunit muscle sympathetic nerve activity compared with the normal-weight (n=11) and obese (n=11) people with normal blood pressure (65+/-4 versus 47+/-6 bursts per 100 heartbeats, P<0.01 in the normal-weight groups and 68+/-4 versus 53+/-3 bursts per 100 beats, P<0.01 in the obese groups). Sympathetic activation in normal-weight hypertension was characterized by increased firing rate of single vasoconstrictor fibers (70+/-8 versus 28+/-3 spikes per 100 beats; P<0.001), increased firing probability per heartbeat (39+/-3% versus 20+/-3%; P<0.001), and higher incidence of multiple spikes per heartbeat (30+/-4% versus 17+/-4%; P<0.05). Sympathetic activation in obesity-related hypertension differed, involving recruitment of previously silent fibers, which fired at a normal rate. The pattern of sympathetic activation in normal-weight and obesity-related hypertension differs in terms of both the firing characteristics of individual sympathetic fibers and the sympathetic outflows involved. The underlying central nervous system mechanism and the adverse consequences of the 2 modes of sympathetic activation may differ.