Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologisc... more Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologische Diagnostik auch bei proktologisch-urologischen Fragestellungen sinnvoll. Neurophysiologische Untersuchungsmethoden wie Bulbokavernosus- und Analreflexmessung, Beckenboden-EMG, PNTML (pudendal nerve terminal motor latency) und motorisch evozierte Potentiale (MEP) haben sich als Standard bei der Untersuchung der somatomotorischen Versorgung im anorektalen bzw. urogenitalen Bereich etabliert. Die Pudendus-SSEP (somatosensibel evozierte Potentiale) hingegen stellen eine valide Methode zur Untersuchung der somatosensiblen Afferenzen aus dem Pudendusgebiet dar. SSEP, die nach Reizung peripherer Nerven über dem Rückenmark und Kortex mittels Oberflächenelektroden abgeleitet werden können, gehören seit Jahren zum Standard klinisch-neurophysiologischer Diagnostik. Sie werden zum objektiven Nachweis und zur Differentialdiagnose bzw. Lokalisation von Erkrankungen des peripheren und zentralen Nervensystems eingesetzt. Die Anwendung der SSEP auf die nervalen Strukturen des Pudendusgebietes kann zusätzliche Informationen bei der Diagnose proktologischer Erkrankungen wie der Stuhlinkontinenz liefern. Dieser Artikel soll einen kurzen Einblick in die Grundlagen, Methodik, Normwerte, Einsatzmöglichkeiten und Aussagekraft der Pudendus-SSEP geben. Apart from the patient's history of illness and the clinical examination, neurophysiological investigations are important in proctological-urological disorders. Neurophysiological methods like pelvic floor EMG, bulbocavernous and anal reflex, PNTML (pudendal nerve terminal motor latency) and the motor evoked potentials (MEP) are well established in the investigation of somatomotor innervation of the anorectal and urogenital region. The pudendal somatosensible evoked potentials (SSEP) represent a valid neurophysiological tool for investigation of the somatosensory pathways from the pudendal region. SSEP are recorded at spinal levels and at the cortex via surface electrodes after stimulation of peripheral nerves. SSEP are used to provide electrophysiological evidence for lesions involved in the pathogenesis of proctological disorders such as anal incontinence. This article gives a brief review of the basics, methods, normal values and indications of pudendal SSEP.
Bei der Analfissur liegt ein schmerzbedingt reflektorisch gesteigerter Analsphinktertonus vor, de... more Bei der Analfissur liegt ein schmerzbedingt reflektorisch gesteigerter Analsphinktertonus vor, der ein Abheilen der Ulzeration verhindert. Botulinumtoxininjektionen führen über eine Hemmung der präsynaptischen Acetylcholinfreisetzung zu einer innerhalb von etwa drei Monaten reversiblen, schlaffen Lähmung und Atrophie des behandelten Muskels. Zur Quantifizierung der Wirkung von Botulinumtoxininjektionen in den externen Analsphinkter bei Analfissur wurde die Muskelantwort nach elektrischer Stimulation des Nervus pudendus bei 25 Patienten (davon 13 Frauen) im Alter von 21 bis 48 Jahren vor und einen bzw. sechs Monate nach Botulinumtoxininjektion untersucht. Die Botulinumtoxintherapie bestand aus zwei Einzelinjektionen von je 0, 1 ml gelöstem Toxin, entsprechend 2,5 bzw. 5 Einheiten Botox® (Allergan, San Francisco, USA), beidseitig der Analfissur. Vor der Injektion betrug die mittlere Latenz 2,1±0,18 ms, die mittlere Amplitude 890±280 μV. Während die Latenz durch die Botulinumtoxininjektion nicht signifikant beeinflußt wurde, war die Amplitude der Muskelaktionspotentiale einen Monat nach Injektion auf 433±130 μV reduziert. Nach einem halben Jahr erreichten die Amplituden wieder ein normales Niveau (695±128 μV), signifikant unterschiedlich zu den Ein-Monats-Werten nach Toxinbehandlung, jedoch ohne signifikante Unterschiede verglichen mit den Ausgangswerten vor Therapiebeginn. Die Untersuchung erlaubt eine Quantifizierung des klinischen Befunds der reversiblen Atrophie der Musculus sphincter ani externus. In anal fissurilly pain-triggered, reflectore, increased anal sphincter tone prevents healing of the ulceration. Botuline toxin injections cause a reversible flaccid paresis and atrophy of the injected muscle via inhibition of presynaptical acetylcholine release for about 3 months. To quantify the efficacy of botuline toxin injections into the external anal sphincter for the treatment of anal fissure, the muscle response after electrical stimulation of the pudendal nerve was recorded before, 1 and 6 months after toxin injection in 25 patients (13 women) ranging from 21 to 48 years age. 0.1 ml soluble toxin corresponding 2.5 and 5 Units Botox® respectively (Allergan, San Francisco, USA) were injected at both sides of the anal fissure. Before injection, the mean latency was 2.1 ± 0.18 ms, mean amplitude 0.89±0.28 mV. Even though latency was not significantly influenced by botuline toxin injection, the amplitude of the muscle action potentials 1 month after the injection was reduced to 0.433±0.13 mV. Half a year later, the amplitudes had returned to normal values (0.695±0.128 mV). There was no significant difference compared to base line amplitudes, but a significant difference compared to amplitudes measured 1 month after treatment with the toxin. The examination allows to quantify the reversible atrophy of the external anal sphincter.
Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologisc... more Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologische Diagnostik auch bei proktologisch-urologischen Fragestellungen sinnvoll. Neurophysiologische Untersuchungsmethoden wie Bulbokavernosus- und Analreflexmessung, Beckenboden-EMG, PNTML (pudendal nerve terminal motor latency) und motorisch evozierte Potentiale (MEP) haben sich als Standard bei der Untersuchung der somatomotorischen Versorgung im anorektalen bzw. urogenitalen Bereich etabliert. Die Pudendus-SSEP (somatosensibel evozierte Potentiale) hingegen stellen eine valide Methode zur Untersuchung der somatosensiblen Afferenzen aus dem Pudendusgebiet dar. SSEP, die nach Reizung peripherer Nerven über dem Rückenmark und Kortex mittels Oberflächenelektroden abgeleitet werden können, gehören seit Jahren zum Standard klinisch-neurophysiologischer Diagnostik. Sie werden zum objektiven Nachweis und zur Differentialdiagnose bzw. Lokalisation von Erkrankungen des peripheren und zentralen Nervensystems eingesetzt. Die Anwendung der SSEP auf die nervalen Strukturen des Pudendusgebietes kann zusätzliche Informationen bei der Diagnose proktologischer Erkrankungen wie der Stuhlinkontinenz liefern. Dieser Artikel soll einen kurzen Einblick in die Grundlagen, Methodik, Normwerte, Einsatzmöglichkeiten und Aussagekraft der Pudendus-SSEP geben. Apart from the patient's history of illness and the clinical examination, neurophysiological investigations are important in proctological-urological disorders. Neurophysiological methods like pelvic floor EMG, bulbocavernous and anal reflex, PNTML (pudendal nerve terminal motor latency) and the motor evoked potentials (MEP) are well established in the investigation of somatomotor innervation of the anorectal and urogenital region. The pudendal somatosensible evoked potentials (SSEP) represent a valid neurophysiological tool for investigation of the somatosensory pathways from the pudendal region. SSEP are recorded at spinal levels and at the cortex via surface electrodes after stimulation of peripheral nerves. SSEP are used to provide electrophysiological evidence for lesions involved in the pathogenesis of proctological disorders such as anal incontinence. This article gives a brief review of the basics, methods, normal values and indications of pudendal SSEP.
Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. ... more Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC are responsive to bile salts is unknown. TGR5, a G-protein–coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C-terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2-cells. Apart from Kupffer cells, TGR5 was detected in SEC of rat liver. SEC expressed TGR5 over the entire acinus, whereas endothelial cells of the portal or central veins were not immunoreactive toward TGR5 antibodies. In isolated SEC, TGR5 mRNA and protein were detected by reverse transcription (RT) PCR, immunofluorescence microscopy, and Western blot analysis. Bile salts increased cAMP in isolated SEC and induced mRNA expression of endothelial NO synthase (eNOS), a known cAMP-dependent gene. In addition, bile acids activated eNOS by phosphorylation of eNOS at amino acid position 1177. In line with eNOS activation, bile acids induced NO production in liver slices. This is the first report on the expression of TGR5 in SEC. Conclusion: The data suggest that SEC are directly responsive toward specific bile salts. Regulation of eNOS in SEC by TGR5 connects bile salts with hepatic hemodynamics. This is of particular importance in cholestatic livers when bile salt concentrations are increased. (HEPATOLOGY 2007;45:695–704.)
Naunyn-schmiedebergs Archives of Pharmacology, 2000
Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal act... more Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions; it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have been extensively studied using in vitro brain-slice preparations. A1-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A1-receptors are almost ubiquitous in the brain and affect various K+ (I leak, I AHP), mixed cationic (I h), or Ca2+ currents, through activation of Gi/o-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A2A-receptors are much more localized, their functional role in the striatum is only just emerging. A2B- and A3-receptors may be affected in pathophysiological events, their function is not yet clear. The cAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction).
Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic ... more Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy (HE). As shown in this study, ammonia induces a rapid RNA oxidation in cultured rat astrocytes, vital mouse brain slices, and rat brain in vivo. Ammonia-induced RNA oxidation in cultured astrocytes is reversible and sensitive to MK-801, 1,2-Bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, apocynin, epigallocatechin gallate, and polyphenon 60, suggesting the involvement of N−methyl−D-aspartic acid (NMDA) receptor activation, Ca2+, nicotinamide adenine dinucleotide phosphate, and reduced form (NADPH) oxidase-dependent oxidative stress. Also, hypo-osmolarity, tumor necrosis factor alpha (TNF-α), and diazepam increase RNA oxidation in cultured astrocytes, suggesting that the action of different HE-precipitating factors converges at the level of RNA oxidation. Among the oxidized RNA species, 18S-rRNA and the messenger RNA (mRNA) coding for the glutamate/aspartate transporter (GLAST) were identified. Cerebral RNA oxidation in acutely ammonia-loaded rats in vivo is reversible and predominates in neuronal soma and perivascular astrocyte processes. In neuronal dendrites, oxidized RNA colocalizes with the RNA-binding splicing protein neurooncological ventral antigen (NOVA)-2 within putative RNA transport granules, which are also found in close vicinity to postsynaptic spines. This indicates that oxidized RNA species may participate in postsynaptic protein synthesis, which is a biochemical substrate for learning and memory consolidation. Neuronal and astroglial RNA oxidation increases also in vital mouse brain slices treated with ammonia and TNF-α, respectively. Conclusion: Cerebral RNA oxidation is identified as a not yet recognized consequence of acute ammonia intoxication. RNA oxidation may affect gene expression and local protein synthesis and thereby provide another link between reactive oxygen species (ROS)/reactive nitrogen oxide species (RNOS) production and ammonia toxicity. (HEPATOLOGY 2008.)
High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakeful... more High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.
Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologisc... more Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologische Diagnostik auch bei proktologisch-urologischen Fragestellungen sinnvoll. Neurophysiologische Untersuchungsmethoden wie Bulbokavernosus- und Analreflexmessung, Beckenboden-EMG, PNTML (pudendal nerve terminal motor latency) und motorisch evozierte Potentiale (MEP) haben sich als Standard bei der Untersuchung der somatomotorischen Versorgung im anorektalen bzw. urogenitalen Bereich etabliert. Die Pudendus-SSEP (somatosensibel evozierte Potentiale) hingegen stellen eine valide Methode zur Untersuchung der somatosensiblen Afferenzen aus dem Pudendusgebiet dar. SSEP, die nach Reizung peripherer Nerven über dem Rückenmark und Kortex mittels Oberflächenelektroden abgeleitet werden können, gehören seit Jahren zum Standard klinisch-neurophysiologischer Diagnostik. Sie werden zum objektiven Nachweis und zur Differentialdiagnose bzw. Lokalisation von Erkrankungen des peripheren und zentralen Nervensystems eingesetzt. Die Anwendung der SSEP auf die nervalen Strukturen des Pudendusgebietes kann zusätzliche Informationen bei der Diagnose proktologischer Erkrankungen wie der Stuhlinkontinenz liefern. Dieser Artikel soll einen kurzen Einblick in die Grundlagen, Methodik, Normwerte, Einsatzmöglichkeiten und Aussagekraft der Pudendus-SSEP geben. Apart from the patient's history of illness and the clinical examination, neurophysiological investigations are important in proctological-urological disorders. Neurophysiological methods like pelvic floor EMG, bulbocavernous and anal reflex, PNTML (pudendal nerve terminal motor latency) and the motor evoked potentials (MEP) are well established in the investigation of somatomotor innervation of the anorectal and urogenital region. The pudendal somatosensible evoked potentials (SSEP) represent a valid neurophysiological tool for investigation of the somatosensory pathways from the pudendal region. SSEP are recorded at spinal levels and at the cortex via surface electrodes after stimulation of peripheral nerves. SSEP are used to provide electrophysiological evidence for lesions involved in the pathogenesis of proctological disorders such as anal incontinence. This article gives a brief review of the basics, methods, normal values and indications of pudendal SSEP.
Bei der Analfissur liegt ein schmerzbedingt reflektorisch gesteigerter Analsphinktertonus vor, de... more Bei der Analfissur liegt ein schmerzbedingt reflektorisch gesteigerter Analsphinktertonus vor, der ein Abheilen der Ulzeration verhindert. Botulinumtoxininjektionen führen über eine Hemmung der präsynaptischen Acetylcholinfreisetzung zu einer innerhalb von etwa drei Monaten reversiblen, schlaffen Lähmung und Atrophie des behandelten Muskels. Zur Quantifizierung der Wirkung von Botulinumtoxininjektionen in den externen Analsphinkter bei Analfissur wurde die Muskelantwort nach elektrischer Stimulation des Nervus pudendus bei 25 Patienten (davon 13 Frauen) im Alter von 21 bis 48 Jahren vor und einen bzw. sechs Monate nach Botulinumtoxininjektion untersucht. Die Botulinumtoxintherapie bestand aus zwei Einzelinjektionen von je 0, 1 ml gelöstem Toxin, entsprechend 2,5 bzw. 5 Einheiten Botox® (Allergan, San Francisco, USA), beidseitig der Analfissur. Vor der Injektion betrug die mittlere Latenz 2,1±0,18 ms, die mittlere Amplitude 890±280 μV. Während die Latenz durch die Botulinumtoxininjektion nicht signifikant beeinflußt wurde, war die Amplitude der Muskelaktionspotentiale einen Monat nach Injektion auf 433±130 μV reduziert. Nach einem halben Jahr erreichten die Amplituden wieder ein normales Niveau (695±128 μV), signifikant unterschiedlich zu den Ein-Monats-Werten nach Toxinbehandlung, jedoch ohne signifikante Unterschiede verglichen mit den Ausgangswerten vor Therapiebeginn. Die Untersuchung erlaubt eine Quantifizierung des klinischen Befunds der reversiblen Atrophie der Musculus sphincter ani externus. In anal fissurilly pain-triggered, reflectore, increased anal sphincter tone prevents healing of the ulceration. Botuline toxin injections cause a reversible flaccid paresis and atrophy of the injected muscle via inhibition of presynaptical acetylcholine release for about 3 months. To quantify the efficacy of botuline toxin injections into the external anal sphincter for the treatment of anal fissure, the muscle response after electrical stimulation of the pudendal nerve was recorded before, 1 and 6 months after toxin injection in 25 patients (13 women) ranging from 21 to 48 years age. 0.1 ml soluble toxin corresponding 2.5 and 5 Units Botox® respectively (Allergan, San Francisco, USA) were injected at both sides of the anal fissure. Before injection, the mean latency was 2.1 ± 0.18 ms, mean amplitude 0.89±0.28 mV. Even though latency was not significantly influenced by botuline toxin injection, the amplitude of the muscle action potentials 1 month after the injection was reduced to 0.433±0.13 mV. Half a year later, the amplitudes had returned to normal values (0.695±0.128 mV). There was no significant difference compared to base line amplitudes, but a significant difference compared to amplitudes measured 1 month after treatment with the toxin. The examination allows to quantify the reversible atrophy of the external anal sphincter.
Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologisc... more Neben einer umfangreichen Anamneseerhebung und klinischen Untersuchung ist eine neurophysiologische Diagnostik auch bei proktologisch-urologischen Fragestellungen sinnvoll. Neurophysiologische Untersuchungsmethoden wie Bulbokavernosus- und Analreflexmessung, Beckenboden-EMG, PNTML (pudendal nerve terminal motor latency) und motorisch evozierte Potentiale (MEP) haben sich als Standard bei der Untersuchung der somatomotorischen Versorgung im anorektalen bzw. urogenitalen Bereich etabliert. Die Pudendus-SSEP (somatosensibel evozierte Potentiale) hingegen stellen eine valide Methode zur Untersuchung der somatosensiblen Afferenzen aus dem Pudendusgebiet dar. SSEP, die nach Reizung peripherer Nerven über dem Rückenmark und Kortex mittels Oberflächenelektroden abgeleitet werden können, gehören seit Jahren zum Standard klinisch-neurophysiologischer Diagnostik. Sie werden zum objektiven Nachweis und zur Differentialdiagnose bzw. Lokalisation von Erkrankungen des peripheren und zentralen Nervensystems eingesetzt. Die Anwendung der SSEP auf die nervalen Strukturen des Pudendusgebietes kann zusätzliche Informationen bei der Diagnose proktologischer Erkrankungen wie der Stuhlinkontinenz liefern. Dieser Artikel soll einen kurzen Einblick in die Grundlagen, Methodik, Normwerte, Einsatzmöglichkeiten und Aussagekraft der Pudendus-SSEP geben. Apart from the patient's history of illness and the clinical examination, neurophysiological investigations are important in proctological-urological disorders. Neurophysiological methods like pelvic floor EMG, bulbocavernous and anal reflex, PNTML (pudendal nerve terminal motor latency) and the motor evoked potentials (MEP) are well established in the investigation of somatomotor innervation of the anorectal and urogenital region. The pudendal somatosensible evoked potentials (SSEP) represent a valid neurophysiological tool for investigation of the somatosensory pathways from the pudendal region. SSEP are recorded at spinal levels and at the cortex via surface electrodes after stimulation of peripheral nerves. SSEP are used to provide electrophysiological evidence for lesions involved in the pathogenesis of proctological disorders such as anal incontinence. This article gives a brief review of the basics, methods, normal values and indications of pudendal SSEP.
Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. ... more Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC are responsive to bile salts is unknown. TGR5, a G-protein–coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C-terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2-cells. Apart from Kupffer cells, TGR5 was detected in SEC of rat liver. SEC expressed TGR5 over the entire acinus, whereas endothelial cells of the portal or central veins were not immunoreactive toward TGR5 antibodies. In isolated SEC, TGR5 mRNA and protein were detected by reverse transcription (RT) PCR, immunofluorescence microscopy, and Western blot analysis. Bile salts increased cAMP in isolated SEC and induced mRNA expression of endothelial NO synthase (eNOS), a known cAMP-dependent gene. In addition, bile acids activated eNOS by phosphorylation of eNOS at amino acid position 1177. In line with eNOS activation, bile acids induced NO production in liver slices. This is the first report on the expression of TGR5 in SEC. Conclusion: The data suggest that SEC are directly responsive toward specific bile salts. Regulation of eNOS in SEC by TGR5 connects bile salts with hepatic hemodynamics. This is of particular importance in cholestatic livers when bile salt concentrations are increased. (HEPATOLOGY 2007;45:695–704.)
Naunyn-schmiedebergs Archives of Pharmacology, 2000
Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal act... more Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions; it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have been extensively studied using in vitro brain-slice preparations. A1-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A1-receptors are almost ubiquitous in the brain and affect various K+ (I leak, I AHP), mixed cationic (I h), or Ca2+ currents, through activation of Gi/o-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A2A-receptors are much more localized, their functional role in the striatum is only just emerging. A2B- and A3-receptors may be affected in pathophysiological events, their function is not yet clear. The cAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction).
Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic ... more Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy (HE). As shown in this study, ammonia induces a rapid RNA oxidation in cultured rat astrocytes, vital mouse brain slices, and rat brain in vivo. Ammonia-induced RNA oxidation in cultured astrocytes is reversible and sensitive to MK-801, 1,2-Bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, apocynin, epigallocatechin gallate, and polyphenon 60, suggesting the involvement of N−methyl−D-aspartic acid (NMDA) receptor activation, Ca2+, nicotinamide adenine dinucleotide phosphate, and reduced form (NADPH) oxidase-dependent oxidative stress. Also, hypo-osmolarity, tumor necrosis factor alpha (TNF-α), and diazepam increase RNA oxidation in cultured astrocytes, suggesting that the action of different HE-precipitating factors converges at the level of RNA oxidation. Among the oxidized RNA species, 18S-rRNA and the messenger RNA (mRNA) coding for the glutamate/aspartate transporter (GLAST) were identified. Cerebral RNA oxidation in acutely ammonia-loaded rats in vivo is reversible and predominates in neuronal soma and perivascular astrocyte processes. In neuronal dendrites, oxidized RNA colocalizes with the RNA-binding splicing protein neurooncological ventral antigen (NOVA)-2 within putative RNA transport granules, which are also found in close vicinity to postsynaptic spines. This indicates that oxidized RNA species may participate in postsynaptic protein synthesis, which is a biochemical substrate for learning and memory consolidation. Neuronal and astroglial RNA oxidation increases also in vital mouse brain slices treated with ammonia and TNF-α, respectively. Conclusion: Cerebral RNA oxidation is identified as a not yet recognized consequence of acute ammonia intoxication. RNA oxidation may affect gene expression and local protein synthesis and thereby provide another link between reactive oxygen species (ROS)/reactive nitrogen oxide species (RNOS) production and ammonia toxicity. (HEPATOLOGY 2008.)
High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakeful... more High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.
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