This article is worth reading:
Neuroinflammation, Neuroautoimmunity, and the Co-Morbidities of Complex Regional Pain Syndrome
Quotes:
"Complex Regional Pain Syndrome (CRPS) is associated with non-dermatomal patterns of pain, unusual
movement disorders, and somatovisceral dysfunctions. These symptoms are viewed by some neurologists and psychiatrists as being psychogenic in origin. Recent evidence, however, suggests that an autoimmune attack on self antigens found in the peripheral and central nervous system may underlie a number of CRPS symptoms."
“For a substantial fraction of adult CRPS cases initiation of CRPS may lie in a breakdown of immunologic self-tolerance, and the development of autoantibodies to the β2AR and M2R neurotransmitter receptors. Once autoantibodies have been generated to these neuroantigens in a given individual, an ongoing progression of stereotyped autoimmune-mediated neuroinflammatory responses might become initiated.”
“In CRPS patients, features of central sensitization appear to involve a complex set of neuroinflammatory responses involving NMDA receptors, glial cell activation in the spinal cord as well as the release of pro-inflammatory cytokines from neurons, glia, and leukocytes. Extravasation of leukocytes and exudation of autoantibodies into the parenchyma of the nervous system are key features of central sensitization during a neuroautoimmune attack of the CNS. The autoimmune attack is focused on sites where autoantibodies bind. Autoimmune attack can potentially lead to the loss of GABAergic inhibitory interneurons.”
“Instead of autoimmune-mediated neuroinflammation, the term “medically unexplained symptoms” has often been used to describe sensory, autonomic, and motor symptoms of CRPS patients, even though there is an extensive literature describing neurophysiological pathologies and mechanisms in these patients. There are several inherent difficulties with the psychogenic hypothesis. However, absence of evidence is not evidence of absence. In addition, characteristics such as the speed of onset and remission have also been used to assign symptoms to neurological vs. psychogenic causes, with the assumption that neurological disease processes have a longer timecourse than psychogenic ones. In this regard, rapid onset and rapid remission have often been used as criteria for diagnosing psychogenic movement disorders, even though autoimmune disorders are well know for their cyclic character of remission and relapse.”
“Conclusion
In clinical practice, when an organic explanation cannot be found for functional disorders, psychogenic etiologies are often asserted. However, as the understanding of functional disorders improves, it appears that neuroimmune and neuroinflammatory disorders are much more common than previously thought. Neuroautoimmunity combined with neuroinflammation together provide a viable etiology for the relapsing-remitting chronicity, atypical presentation and intensity of neurological and psychiatric symptoms. When faced with medically unexplained symptoms, health practitioners and patients should actively seek physiological hypotheses, as an alternative to diagnoses of somatoform or conversion disorders. Neuroinflammatory lesions, along with their functional consequences, should always be considered in the differential diagnosis of medically unexplained symptoms, even when commonly used clinical neuroimaging protocols fail to reveal positive evidence of neuroinflammation. When viewing the symptoms of an individual patient, health practitioners should anticipate that a given patient might have a complex, multifocal pattern of neuroinflammation and associated functional symptoms. The presentation of symptoms may be idiosyncratic to that patient, depending on the topographic pattern and severity of neuroinflammation and other variables, often yet undiscovered. However, key mechanistic elements of spreading neuroinflammation could be common to a wide spectrum of patients and disorders. By integrating neuroinflammation and neuroautoimmune concepts into the differential diagnosis of neurological and neuropsychiatric symptoms, a number of functional sensory and motor disorders may become less medically unexplainable than was previously thought. As diagnostic methods continue to improve, it may someday be possible for neuroautoimmuity and neuroinflammation to be commonly assessed as a part of a differential diagnosis of chronic pain syndromes such as CRPS.”
tirsdag den 18. september 2012
torsdag den 13. september 2012
Amerikanske myndigheder har focus på udvikling af lægemidler til ME/CFS
De amerikanske myndigheder US Food and Drug Administration (FDA) har ansvaret for at godkende lægemidler. De sætter nu focus på at fremskynde processen for ME/CFS, således at der kan komme lægemidler til ME/CFS patienter:
Videre oversættelse af FDA's uddybende baggrundsmateriale:
Information for ME/CFS Interessent Telekonference - September 13, 2012
CDER's rolle i Medicin Udvikling:
FDA Center for Drug Evaluation and Research (CDER) er ansvarlig for at sikre, at lægemidler, der markedsføres i USA er sikre og effektive. For at et lægemiddel kan godkendes, skal fordelene opveje risiciene. Oplysningerne for denne risiko/fordel-analyse kommer fra kliniske studier udført af pågældende medicinalfirma. For at teste lægemidlets sundhedsmæssige fordel skal de kliniske undersøgelser evaluere målelige resultater kaldet "endpoints". Eksempler på "endpoints" kunne været et reduceret blodtryk eller det at være i stand til at gå i en øget periode. Bivirkninger af lægemidlet er identificeret som lægemidlet risici.
CDER tester ikke ikke selv lægemidler i kliniske forsøg, da det er op til det enkelte medicinalfirma at bevise, at deres lægemiddel virker sikkert og effektivt. Efter modtagelsen af sådanne oplysninger gennemgår CDER data. CDER udfører kun forskning i lægemiddel kvalitet, sikkerhed og effektivitets standarder. Når lægemidler er frigivet til markedet, overvåger FDA disse lægemidler for uventede sikkerhedsproblemer. Hvis et lægemiddel viser sig at have en uacceptabel risiko, vil offentligheden blive underrettet og sikkerhedsmærkningen kan ændres eller lægemidlet kan fjernes fra markedet.
FDA er forpligtet til at stille lovende lægemidler til rådighed for personer med alvorlige sygdomme så hurtigt som muligt. FDA har flere programmer, der understøtter den hurtige udvikling og revision af disse typer af behandlinger. For eksempel: den fremskyndede godkendelsesproces øger tilgængeligheden af eksperimentelle lægemidler og biologiske produkter baseret på et "endpoint", der sandsynligvis kan forudsige klinisk gavn.
Disse lægemidler er nødt til at behandle alvorlige eller livstruende sygdomme og give meningsfulde og målbare terapeutiske fordele for patienterne i forhold til eksisterende behandlinger. Denne proces imødekommer udækkede medicinske behov og fremskynder gennemgang og godkendelse af ansøgninger for disse produkter. Denne procedure kræver fremtidige undersøgelser for at bekræfte effektiviteten af behandlingen, ellers kan lægemidlet blive fjernet fra markedet.
CDER's mål i ME og CFS Lægemiddel Udvkling.
FDA tager bekymringen om ME og CFS patienter alvorligt, herunder manglen på godkendte behandlinger, og samarbejder med interessenter for at fremme udviklingen af levedygtige behandlingsmuligheder. Gyldige, pålidelige og målbare "endpoints" skal først identificeres, og som repræsenterer den gavn som personer med ME eller CFS har af behandlingen, således at disse "endpoints" kan bruges i kliniske forsøg til at teste lægemiddelbehandlinger.
Der har været debat om konsolideringen af ME og CFS ved at beskrive symptom komplekset. Lægemiddeludviklingen fokuserer på kvantitative mål for gavn af behandlingen (f.eks symptom forbedring), ikke på sygdommens navn. Derfor med henblik på udvikling af lægemidler, er henvisningen til ME/CFS ikke ensbetydende med, at FDA ser de to sygdomme eller syndromer som det samme.
CDER planlægger en række aktiviteter for at undersøge mulighederne for at bringe sikre og effektive ME og CFS lægemidler på markedet, og denne interessent telekonference er begyndelsen på disse tiltag.
FDA vil planlægge en række aktiviteter, fokuseret på udvikling af lægemidler til behandling af symptomerne fra Myalgisk Encephalomyelitis og Chronic Fatigue Syndrome (ME/CFS), for at undersøge:
- Byrden af sygdom, der påvirker livskvaliteten for ME/CFS patienter.
- De kvantitative resultatmål eller "endpoints", der afgør, om sygdomssymptomer forbedres med intervention.
- Hvordan lægemiddeleffektivitet bør testes klinisk baseret på disse endpoints eller målinger.
Videre oversættelse af FDA's uddybende baggrundsmateriale:
Information for ME/CFS Interessent Telekonference - September 13, 2012
CDER's rolle i Medicin Udvikling:
FDA Center for Drug Evaluation and Research (CDER) er ansvarlig for at sikre, at lægemidler, der markedsføres i USA er sikre og effektive. For at et lægemiddel kan godkendes, skal fordelene opveje risiciene. Oplysningerne for denne risiko/fordel-analyse kommer fra kliniske studier udført af pågældende medicinalfirma. For at teste lægemidlets sundhedsmæssige fordel skal de kliniske undersøgelser evaluere målelige resultater kaldet "endpoints". Eksempler på "endpoints" kunne været et reduceret blodtryk eller det at være i stand til at gå i en øget periode. Bivirkninger af lægemidlet er identificeret som lægemidlet risici.
CDER tester ikke ikke selv lægemidler i kliniske forsøg, da det er op til det enkelte medicinalfirma at bevise, at deres lægemiddel virker sikkert og effektivt. Efter modtagelsen af sådanne oplysninger gennemgår CDER data. CDER udfører kun forskning i lægemiddel kvalitet, sikkerhed og effektivitets standarder. Når lægemidler er frigivet til markedet, overvåger FDA disse lægemidler for uventede sikkerhedsproblemer. Hvis et lægemiddel viser sig at have en uacceptabel risiko, vil offentligheden blive underrettet og sikkerhedsmærkningen kan ændres eller lægemidlet kan fjernes fra markedet.
FDA er forpligtet til at stille lovende lægemidler til rådighed for personer med alvorlige sygdomme så hurtigt som muligt. FDA har flere programmer, der understøtter den hurtige udvikling og revision af disse typer af behandlinger. For eksempel: den fremskyndede godkendelsesproces øger tilgængeligheden af eksperimentelle lægemidler og biologiske produkter baseret på et "endpoint", der sandsynligvis kan forudsige klinisk gavn.
Disse lægemidler er nødt til at behandle alvorlige eller livstruende sygdomme og give meningsfulde og målbare terapeutiske fordele for patienterne i forhold til eksisterende behandlinger. Denne proces imødekommer udækkede medicinske behov og fremskynder gennemgang og godkendelse af ansøgninger for disse produkter. Denne procedure kræver fremtidige undersøgelser for at bekræfte effektiviteten af behandlingen, ellers kan lægemidlet blive fjernet fra markedet.
CDER's mål i ME og CFS Lægemiddel Udvkling.
FDA tager bekymringen om ME og CFS patienter alvorligt, herunder manglen på godkendte behandlinger, og samarbejder med interessenter for at fremme udviklingen af levedygtige behandlingsmuligheder. Gyldige, pålidelige og målbare "endpoints" skal først identificeres, og som repræsenterer den gavn som personer med ME eller CFS har af behandlingen, således at disse "endpoints" kan bruges i kliniske forsøg til at teste lægemiddelbehandlinger.
Der har været debat om konsolideringen af ME og CFS ved at beskrive symptom komplekset. Lægemiddeludviklingen fokuserer på kvantitative mål for gavn af behandlingen (f.eks symptom forbedring), ikke på sygdommens navn. Derfor med henblik på udvikling af lægemidler, er henvisningen til ME/CFS ikke ensbetydende med, at FDA ser de to sygdomme eller syndromer som det samme.
CDER planlægger en række aktiviteter for at undersøge mulighederne for at bringe sikre og effektive ME og CFS lægemidler på markedet, og denne interessent telekonference er begyndelsen på disse tiltag.
søndag den 9. september 2012
TRP Ion Channels
The cell communicates with the surroundings via receptors in the cell surface. Based on structural and functional similarities, membrane receptors are mainly divided into 3 classes: The ion channel-linked receptor, the enzyme-linked receptor and G protein-coupled receptor. Reference wikipedia.
TRP channels (transient receptor potential channels) - the family is subdivided into 6 subfamilies based on homology:
- TRPC1-7, Canonical
- TRPV1-6, Vanilloid
- TRPM1-8, Melastatin
- TRPP1-3, Polycystin
- TRPML1-3, Mucolipin
- TRPA1, Ankyrin
This TRP superfamily of ion channels play a crucial role in a broad range of sensory functions including vision, taste, olfaction, hearing, touch, pain and thermosensation. Reference.
Alan R. Light, Charles J. Vierck, and Kathleen C. Light have written about TRPV1s possible role in ME/CFS and comorbidities in Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes.
I find TRP ion channels interesting because they are found in dorsal root ganglia and they are suspected to be involved with microglia activation as I wrote about in my last blogs. Pathophysiological roles of transient receptor potential channels in glial cells.
And TRP ion channel interact with G protein coupled receptors, which Professor Don Staines has hypothesised is involved in ME. Two to tango: GPCR oligomers and GPCR-TRP channel interactions in nociception.
Recent research shows that TRPV1 is a stress response protein in the central nervous system. TRPV1 is emerging as a key mediator of CNS function through modulation of both glial and neuronal activity. Growing evidence has suggested that TRPV1 can mediate a variety of pathways from glial reactivity and cytokine release to synaptic transmission and plasticity. Increasing evidence shows that TRPV1 is as a regulator of CNS function in response to stress. This article also suggests that TRPV1 is implicated in dopamine and glutamte release, and within the dorsal root ganglion, TRPV1 expression is localized to the C-and Aδ- fibers. Here, channel activation leads to calcium elevations and subsequent release of neuropeptides including calcitonin-gene-related peptide and substance P.
TRP channels is also considered to be involved in neropathic pain in diabetes: Role of Oxidative Stress and Ca(2+) Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels.
And in bladder pain syndrome: Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: Implication for the pathogenesis of interstitial cystitis/bladder pain syndrome.
And a lot of other diseases: Transient receptor potential cation channels in disease.
There is a book about TRP Channels here: TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.
TRPA1 Mediates Mechanical Sensitization in Nociceptors during Inflammation:
"Inflammation is a part of the body's natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation....Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice."
TRPA1 Mediates Mechanical Sensitization in Nociceptors during Inflammation:
"Inflammation is a part of the body's natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation....Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice."
lørdag den 8. september 2012
Inflammation in Dorsal Root Ganglia
I found this little interview at: Science Interview.
"Inflammation in Chronic Fatigue"
Dr. Abhijit Chaudhuri, Queen's Hospital, Romford and Professor Hugh Perry, Southampton University
Hermed en oversættelse af noget af ovennævnte interview:
Louise (interviewer): ...CFS blev første gang defineret i 1988, men vi ved stadig ikke hvordan eller hvorfor, virusinfektioner synes at være i stand til at udløse denne lidelse. Og faktisk har vi meget lidt idé om, hvad der forårsager patienternes symptomer. Obduktioner er et af de bedste steder at starte. Et team med Dr. Dominic O'Donovan fra Addenbrooke Hospital i Cambridge og Dr. Abhijit Chaudhuri fra Queens Hospital i Romford har kigget på nervesystemet fra fire patienter, der led af CFS. Her er hvad Dr. Chaudhuri har at sige.
Abhijit: Det er helt klart, at der er noget unormalt, der er rettet mod bestemte dele af nervesystemet.
Louise: Hvilke abnormiteter fandt de så? I den første patient Dr. O'Donovan undersøgte, fandt han et stort antal aflejringer, der kaldes corpora amylacea, spredt over hele hjernen og rygmarven. Professor Perry er professor i eksperimentel neuropatologi ved Southampton University og selv om han ikke var involveret i undersøgelsen, har han givet os sin vurdering af resultaterne.
Hugh: Corpora amylacea er små aflejringer, der ses i hjernen hos en hel masse mennesker, der har forskellige typer af neurodegenerativ sygdom. Netop hvad deres betydning er, synes jeg, er rigtig uklart, bortset fra at de er normalt forbundet med vævsdegeneration. Det kunne være tegn på en degenerativ proces.
Louise: Dette fund tyder på, at nervecellerne i patientens hjerne og rygmarv blev beskadiget eller ødelagt, mens han stadig var i live. Men det fortæller os intet om, hvad der forårsagede denne skade. Den næste patient, som forskerne så på, giver måske svaret. Der var inflammation i dorsale rodganglier. Disse strukturer nær, hvor de sensoriske nerver fører ind i rygmarve, indeholder normalt kun nerveceller og nogle få støttestrukturer. Men Dr. O'Donovan fandt immunceller infiltrerer i ganglierne. Disse immunceller, som kaldes cytotoksiske T-celler, dræber normalt andre celler i kroppen for at kontrollere virusinfektioner eller fjerne beskadigede celler. Tidligere arbejde har vist, at patienter med CFS ofte har flere af disse T-celler i blodet. Men hvad betyder det, hvis de er infiltrerede i dorsale rodsganglier?
Hugh: Dorsalrodsganglier er de neuroner, der formidler sensorisk information ind i rygmarven, og sensorisk information omfatter smerte, temperatur, tryk, og så videre. Smerte information er det vigtigste af alt i denne sammenhæng, da vi ved, at der er mange mennesker med CFS, der klager over smerter i deres ekstremiteter. Så, for derefter at finde tegn på inflammation omkring neuronerne (hvilket er, hvad T-cellerne fortæller os), er i sig selv meget interessant.
Louise: Både Professor Perry og Dr. O'Donovan er enige om, at denne inflammation kan forårsage de muskel-og ledsmerter, som mennesker med CFS ofte har, og at det kan være deres eget immunsystem, som angriber disse nerver i den dorsale rodganglier. Og da Dr. O'Donovan farvede dorsalrodsganglierne til påvisning af T-celler fra to andre patienter, fandt han den samme inflammation, dog mildere. Så alle de CFS patienter, der indgik i denne undersøgelse havde enten aktiv inflammation i deres perifere nervesystem eller tegn på en degenerativ proces i deres rygmarv og hjerne. Men det er ikke klart, hvordan eller om, inflammationen er forbundet med den degeneration, der blev fundet hos det første patient, især da det er påvirkning af forskellige dele af nervesystemet. Og med kun fire patienter, er dette et meget lille studie og meget mere arbejde er nødvendigt, førend at vi kan være sikre på, hvad disse foreløbige resultater kan betyde. Navnlig er det meget vigtigt, at vi sammenligner CFS patienter med personer, som ikke har sygdommen. Denne del af nervesystemet undersøges ikke normalt i detaljer under en obduktion. Alligevel kunne disse resultater være et interessant udgangspunkt for fremtidig forskning som Dr. Chaudhuri påpeger ...
Abhijit: Det faktum, at vi ser noget unormalt bør overbevise os om at foretage en mere fokuseret forskning i de neuroimmunologiske aspekter af sygdommen.
Louise: Og kunne det faktum, at T-celler er involveret i at kontrollere en virusinfektion som mononucleose være bindeled mellem infektioner og CFS? Vi må vente og se.
Slut på oversættelse af interview.
Vil du vide mere:
Lille artikel om smerteforskning og dorsalrodsganglier
"Inflammation in Chronic Fatigue"
Dr. Abhijit Chaudhuri, Queen's Hospital, Romford and Professor Hugh Perry, Southampton University
Hermed en oversættelse af noget af ovennævnte interview:
Louise (interviewer): ...CFS blev første gang defineret i 1988, men vi ved stadig ikke hvordan eller hvorfor, virusinfektioner synes at være i stand til at udløse denne lidelse. Og faktisk har vi meget lidt idé om, hvad der forårsager patienternes symptomer. Obduktioner er et af de bedste steder at starte. Et team med Dr. Dominic O'Donovan fra Addenbrooke Hospital i Cambridge og Dr. Abhijit Chaudhuri fra Queens Hospital i Romford har kigget på nervesystemet fra fire patienter, der led af CFS. Her er hvad Dr. Chaudhuri har at sige.
Abhijit: Det er helt klart, at der er noget unormalt, der er rettet mod bestemte dele af nervesystemet.
Louise: Hvilke abnormiteter fandt de så? I den første patient Dr. O'Donovan undersøgte, fandt han et stort antal aflejringer, der kaldes corpora amylacea, spredt over hele hjernen og rygmarven. Professor Perry er professor i eksperimentel neuropatologi ved Southampton University og selv om han ikke var involveret i undersøgelsen, har han givet os sin vurdering af resultaterne.
Hugh: Corpora amylacea er små aflejringer, der ses i hjernen hos en hel masse mennesker, der har forskellige typer af neurodegenerativ sygdom. Netop hvad deres betydning er, synes jeg, er rigtig uklart, bortset fra at de er normalt forbundet med vævsdegeneration. Det kunne være tegn på en degenerativ proces.
Louise: Dette fund tyder på, at nervecellerne i patientens hjerne og rygmarv blev beskadiget eller ødelagt, mens han stadig var i live. Men det fortæller os intet om, hvad der forårsagede denne skade. Den næste patient, som forskerne så på, giver måske svaret. Der var inflammation i dorsale rodganglier. Disse strukturer nær, hvor de sensoriske nerver fører ind i rygmarve, indeholder normalt kun nerveceller og nogle få støttestrukturer. Men Dr. O'Donovan fandt immunceller infiltrerer i ganglierne. Disse immunceller, som kaldes cytotoksiske T-celler, dræber normalt andre celler i kroppen for at kontrollere virusinfektioner eller fjerne beskadigede celler. Tidligere arbejde har vist, at patienter med CFS ofte har flere af disse T-celler i blodet. Men hvad betyder det, hvis de er infiltrerede i dorsale rodsganglier?
Hugh: Dorsalrodsganglier er de neuroner, der formidler sensorisk information ind i rygmarven, og sensorisk information omfatter smerte, temperatur, tryk, og så videre. Smerte information er det vigtigste af alt i denne sammenhæng, da vi ved, at der er mange mennesker med CFS, der klager over smerter i deres ekstremiteter. Så, for derefter at finde tegn på inflammation omkring neuronerne (hvilket er, hvad T-cellerne fortæller os), er i sig selv meget interessant.
Louise: Både Professor Perry og Dr. O'Donovan er enige om, at denne inflammation kan forårsage de muskel-og ledsmerter, som mennesker med CFS ofte har, og at det kan være deres eget immunsystem, som angriber disse nerver i den dorsale rodganglier. Og da Dr. O'Donovan farvede dorsalrodsganglierne til påvisning af T-celler fra to andre patienter, fandt han den samme inflammation, dog mildere. Så alle de CFS patienter, der indgik i denne undersøgelse havde enten aktiv inflammation i deres perifere nervesystem eller tegn på en degenerativ proces i deres rygmarv og hjerne. Men det er ikke klart, hvordan eller om, inflammationen er forbundet med den degeneration, der blev fundet hos det første patient, især da det er påvirkning af forskellige dele af nervesystemet. Og med kun fire patienter, er dette et meget lille studie og meget mere arbejde er nødvendigt, førend at vi kan være sikre på, hvad disse foreløbige resultater kan betyde. Navnlig er det meget vigtigt, at vi sammenligner CFS patienter med personer, som ikke har sygdommen. Denne del af nervesystemet undersøges ikke normalt i detaljer under en obduktion. Alligevel kunne disse resultater være et interessant udgangspunkt for fremtidig forskning som Dr. Chaudhuri påpeger ...
Abhijit: Det faktum, at vi ser noget unormalt bør overbevise os om at foretage en mere fokuseret forskning i de neuroimmunologiske aspekter af sygdommen.
Louise: Og kunne det faktum, at T-celler er involveret i at kontrollere en virusinfektion som mononucleose være bindeled mellem infektioner og CFS? Vi må vente og se.
Slut på oversættelse af interview.
Vil du vide mere:
Lille artikel om smerteforskning og dorsalrodsganglier
tirsdag den 4. september 2012
Microglia priming - a role in ME?
Professor Hugh Perry from University of Southampton gave an absolut wonderful presentation on the INVEST in ME conference in June 2012. I have just seen his prensentation on the conference DVD - twice!!
(I can highly recommend the DVDs from the conference. You need to have a little medical insight to understand them. You can buy them here.)
Professor Hugh Perry is not a ME researcher, but is a professor of experimental neuropathology. He researches in Inflammation in the CNS and its contribution to Neurological Disease.
From his article Contribution of systemic inflammation to chronic neurodegeneration:
"Systemic infection or inflammation gives rise to signals that communicate with the brain and leads to changes in metabolism and behaviour collectively known as sickness behaviour. In healthy young individuals, these changes are normally transient with no long-term consequences. The microglia are involved in the immune to brain signalling pathways. In the aged or diseased brain, the microglia have a primed phenotype as a consequence of changes in their local microenvironment. Systemic inflammation impacts on these primed microglia and switches them from a relatively benign to an aggressive phenotype with the enhanced synthesis of pro-inflammatory mediators. Recent evidence suggests that systemic inflammation contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and may accelerate disease progression. The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention. Prompt treatment of systemic inflammation or blockade of signalling pathways from the periphery to the brain may help to slow neurodegeneration and improve the quality of life for individuals suffering from chronic neurodegenerative disease."
If ME is a neurodegererative disease with microglia priming, it could explain why ME patients are getting worse after an infection.
I looked for more articles about microglia priming:
The conclusion from this study Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia:
"These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease."
The abstract from this study Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses:
"Acute and chronic stress sensitizes or "primes" the neuroinflammatory response to a subsequent pro-inflammatory challenge. While prior evidence shows that glucocorticoids (GCs) play a pivotal role in stress-induced potentiation of neuroinflammatory responses, it remains unclear whether stress-induced GCs sensitize the response of key CNS immune substrates (i.e. microglia) to pro-inflammatory stimuli. An ex vivo approach was used to address this question. Here, stress-induced GC signaling was manipulated in vivo and hippocampal microglia challenged with the pro-inflammatory stimulus LPS ex vivo. Male Sprague-Dawley rats were either pretreated in vivo with the GC receptor antagonist RU486 or adrenalectomized (ADX). Animals were then exposed to an acute stressor (inescapable tailshock; IS) and 24 h later hippocampal microglia were isolated and challenged with LPS to probe for stress-induced sensitization of pro-inflammatory responses. Prior exposure to IS resulted in a potentiated pro-inflammatory cytokine response (e.g. IL-1β gene expression) to LPS in isolated microglia. Treatment in vivo with RU486 and ADX inhibited or completely blocked this IS-induced sensitization of the microglial pro-inflammatory response. The present results suggest that stress-induced GCs function to sensitize the microglial pro-inflammatory response (IL-1β, IL-6, NFκBIα) to immunologic challenges."
This is also interesting Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures:
"Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures."
And this Beta-adrenergic receptor activation primes microglia cytokine production:
"Exaggerated pro-inflammatory cytokine production by primed microglia is thought to mediate pathology during stress, aging, and neurodegeneration. Recently, it was demonstrated that beta-adrenergic receptor (β-AR) antagonism prevents priming of microglia in mice exposed to chronic stress. To determine if β-AR stimulation is sufficient to prime microglia, rats were intra-cerebroventricularly administered isoproterenol (β-AR agonist) or vehicle and 24h later hippocampal microglia were placed in culture with media or LPS. Prior isoproterenol treatment significantly enhanced IL-1β and IL-6, but not TNF-α production following LPS stimulation. These data suggest that central β-AR stimulation is sufficient to prime microglia cytokine responses."
(I can highly recommend the DVDs from the conference. You need to have a little medical insight to understand them. You can buy them here.)
Professor Hugh Perry is not a ME researcher, but is a professor of experimental neuropathology. He researches in Inflammation in the CNS and its contribution to Neurological Disease.
From his article Contribution of systemic inflammation to chronic neurodegeneration:
"Systemic infection or inflammation gives rise to signals that communicate with the brain and leads to changes in metabolism and behaviour collectively known as sickness behaviour. In healthy young individuals, these changes are normally transient with no long-term consequences. The microglia are involved in the immune to brain signalling pathways. In the aged or diseased brain, the microglia have a primed phenotype as a consequence of changes in their local microenvironment. Systemic inflammation impacts on these primed microglia and switches them from a relatively benign to an aggressive phenotype with the enhanced synthesis of pro-inflammatory mediators. Recent evidence suggests that systemic inflammation contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and may accelerate disease progression. The normal homeostatic role that microglia play in signalling about systemic infections and inflammation becomes maladaptive in the aged and diseased brain and this offers a route to therapeutic intervention. Prompt treatment of systemic inflammation or blockade of signalling pathways from the periphery to the brain may help to slow neurodegeneration and improve the quality of life for individuals suffering from chronic neurodegenerative disease."
If ME is a neurodegererative disease with microglia priming, it could explain why ME patients are getting worse after an infection.
I looked for more articles about microglia priming:
The conclusion from this study Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia:
"These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease."
The abstract from this study Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses:
"Acute and chronic stress sensitizes or "primes" the neuroinflammatory response to a subsequent pro-inflammatory challenge. While prior evidence shows that glucocorticoids (GCs) play a pivotal role in stress-induced potentiation of neuroinflammatory responses, it remains unclear whether stress-induced GCs sensitize the response of key CNS immune substrates (i.e. microglia) to pro-inflammatory stimuli. An ex vivo approach was used to address this question. Here, stress-induced GC signaling was manipulated in vivo and hippocampal microglia challenged with the pro-inflammatory stimulus LPS ex vivo. Male Sprague-Dawley rats were either pretreated in vivo with the GC receptor antagonist RU486 or adrenalectomized (ADX). Animals were then exposed to an acute stressor (inescapable tailshock; IS) and 24 h later hippocampal microglia were isolated and challenged with LPS to probe for stress-induced sensitization of pro-inflammatory responses. Prior exposure to IS resulted in a potentiated pro-inflammatory cytokine response (e.g. IL-1β gene expression) to LPS in isolated microglia. Treatment in vivo with RU486 and ADX inhibited or completely blocked this IS-induced sensitization of the microglial pro-inflammatory response. The present results suggest that stress-induced GCs function to sensitize the microglial pro-inflammatory response (IL-1β, IL-6, NFκBIα) to immunologic challenges."
This is also interesting Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures:
"Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures."
And this Beta-adrenergic receptor activation primes microglia cytokine production:
"Exaggerated pro-inflammatory cytokine production by primed microglia is thought to mediate pathology during stress, aging, and neurodegeneration. Recently, it was demonstrated that beta-adrenergic receptor (β-AR) antagonism prevents priming of microglia in mice exposed to chronic stress. To determine if β-AR stimulation is sufficient to prime microglia, rats were intra-cerebroventricularly administered isoproterenol (β-AR agonist) or vehicle and 24h later hippocampal microglia were placed in culture with media or LPS. Prior isoproterenol treatment significantly enhanced IL-1β and IL-6, but not TNF-α production following LPS stimulation. These data suggest that central β-AR stimulation is sufficient to prime microglia cytokine responses."
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