Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Gene Expression Changes and Brain Plasticity after Experimental Stroke

Rickhag, Mattias LU (2007)
Abstract
Stroke is the most common life-threatening neurological disease and ranks as the third leading cause of death in major industrialized countries. It is also the leading cause of serious long-term disability and about sixty percent of survivors have disabilities in their extremities. Recovery of certain neurological functions occurs over time, which has been attributed to endogenous restorative processes in areas adjacent and remote from the infarct area. The area adjacent to infarct, the peri-infarct area, shows activation of processes pertinent for recovery such as enhanced cellular excitability and axonal sprouting. The major objective of this thesis has been to unravel some aspects of functional recovery following stroke. In Paper I, we... (More)
Stroke is the most common life-threatening neurological disease and ranks as the third leading cause of death in major industrialized countries. It is also the leading cause of serious long-term disability and about sixty percent of survivors have disabilities in their extremities. Recovery of certain neurological functions occurs over time, which has been attributed to endogenous restorative processes in areas adjacent and remote from the infarct area. The area adjacent to infarct, the peri-infarct area, shows activation of processes pertinent for recovery such as enhanced cellular excitability and axonal sprouting. The major objective of this thesis has been to unravel some aspects of functional recovery following stroke. In Paper I, we undertook a comprehensive investigation of gene expression changes in the peri-infarct area during the first 24 h after insult using large-scale array technology. Several genes associated with tissue regeneration and recovery, were activated early after the ischemic insult. In particular, we identified genes related to lipid transport and myelin formation as well as genes involved in synaptic plasticity. This suggests that parallel to cell death signaling and ensuing cell death in severely injured areas, repair processes are induced in the adjacent surviving areas. In Paper II and II, we characterized expression of transcriptional regulators/effectors most likely implicated in adaptation/stress response of the peri-infarct area.



The second part of the thesis focused on the long-term recovery period (0-30 days) following stroke. In Paper IV, we investigated the role of Apolipoprotein D, a transport protein known to be important for lipid trafficking. ApoD accumulated along the rim of the infarct during the first week of recovery and was localized to oligodendrocytes. We believe that this expression is associated with regeneration of the peri-infarct area and ApoD may function as a lipid carrier providing myelinating oligodendrocytes with cholesterol for axonal regeneration. Further, housing animals in an enriched setting during the post-ischemic period elicited increased levels of ApoD and this was associated with an improved functional recovery. In Paper V, we showed that administration of a receptor ligand, initiated two days following insult, enhanced functional recovery. The mechanisms of this recovery enhancing effects were attributed to stimulation of axonal outgrowth and possibly regulation of lipid transport in the peri-infarct area. The last two studies reveal novel aspects of recovery by emphasizing the importance of lipid trafficking for formation of new connections of the brain.



Overall, this thesis shows that the injured brain activates repair processes early after an ischemic insult and that these events can be stimulated by either pharmacology and/or enriched environment. Delaying commencement of pharmacological treatment for days after injury still results in an improvement in functional outcome. This finding together with other reports strongly argue that the therapeutic time window after stroke is much more extensive than previously believed. Eligible future stroke therapies must consider beyond the acute phase of cell death and focus on enhancement of post-injury plasticity. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Stroke utgör den tredje vanligaste dödsorsaken i västvärlden och är dessutom huvudorsak till långvarigt handikapp hos vuxna individer. Det stora antalet överlevande men handikappade individer utgör ett omfattande problem för samhället inte bara i form av ekonomiska resurser utan även vad gäller personliga trauma. Den kliniska termen stroke omfattar patologiska tillstånd där hjärnans blodcirkulation störs vilket leder till vävnadsdöd och förlust av neurologiska funktioner. Trots det omfattande vävnadsbortfallet uppvisar flertalet överlevande en spontan återhämtning av vissa funktioner. En fördjupad förståelse av de cellulära processer som ligger till grund för denna funktionsåterhämtning kan skapa... (More)
Popular Abstract in Swedish

Stroke utgör den tredje vanligaste dödsorsaken i västvärlden och är dessutom huvudorsak till långvarigt handikapp hos vuxna individer. Det stora antalet överlevande men handikappade individer utgör ett omfattande problem för samhället inte bara i form av ekonomiska resurser utan även vad gäller personliga trauma. Den kliniska termen stroke omfattar patologiska tillstånd där hjärnans blodcirkulation störs vilket leder till vävnadsdöd och förlust av neurologiska funktioner. Trots det omfattande vävnadsbortfallet uppvisar flertalet överlevande en spontan återhämtning av vissa funktioner. En fördjupad förståelse av de cellulära processer som ligger till grund för denna funktionsåterhämtning kan skapa helt nya behandlingsmöjligheter för stroke.



Syftet med denna avhandling har varit att studera mekanismer med betydelse för återhämtning av sensori-motoriska funktioner efter stroke. Under återhämtnings-fasen efter stroke aktiverar hjärnan regenerativa processer både i den skadade och i den intakta hemisfären. Det överlevande området intill infarkten, peri-infarktregionen, visar på en anpassning till skadan genom att aktivera cellulära processer som utväxt av nervtrådar och andra strukturella förändringar vilka bidrar till återhämtningen. I avhandlingens först del (arbete I-III) har vi i detalj kartlagt genförändringar i peri-infarktområdet under det första dygnet efter skadan. Denna omfattande studie av genförändringar efter stroke avslöjade att gener med betydelse för regeneration av skadad vävnad och funktionell återhämtning aktiveras redan under det första dygnet efter skadan. Vi fann att åtskilliga gener var relaterade till myeliniseringprocessen och lipidtransport. Detta visar på att samtidigt som en aktivering av celldödssignalering sker så triggas också reparationssystem igång, för att hjärnan ska kunna anpassa sig och överleva skadan.



I avhandlingens andra del (arbete IV-V) visade vi att ett protein som fungerar som transportör av lipider var kraftigt aktiverat under den första veckan efter skadan. Proteinet, Apolipoprotein D, var lokaliserat längs med hela gränszonen mellan intakt och skadad vävnad. Majoriteten av celler som innehöll ApoD utgjordes av en glial celltyp, oligodendrocyter. Tidigare studier har visat att oligodendrocyter ansamlas utanför infarktgränsen och vi tror att dessa celler medverkar i remyelinisering/omstrukturering av nervförbindelser i detta område. Det har även visats att ApoD har stor betydelse för distribution av kolesterol och lipider. Huvuddelen av hjärnans förråd av kolesterol finns nämligen i myelinet. Vår hypotes är att efter stroke återanvänds kolesterol och lipider från döende celler vid syntes av nya membran för axonal regeneration. Denna återanvändningsprocess av lipider och kolesterol har beskrivits efter perifera nervskador. Vi anser vidare att dessa fynd tyder på att lipiddistribution skulle kunna spela en ytterst viktig roll för regeneration av vävnad efter stroke.



I denna avhandling fann vi att i djurexperimentella modeller återfås sensori-motoriska funktioner inom 2-4 veckor efter stroke. I den sista studien användes farmakologi för att stimulera funktionell återhämtning och i detta fallet rörde det sig om en ligand för sigma-1 receptorn, SA4503. Fyra veckors behandling med denna substans hade en positiv effekt på sensori-motorisk funktion. Cellulära effekter av denna substans var tydliga med en ökad utväxt av nervtrådar och även dendritförgreningar vilket observerades i cellkulturer. Behandling med denna substans påbörjades två dagar efter skadan vilket tyder på att det terapeutiska tidsfönstret efter stroke är mycket bredare än man tidigare antagit. Två dagar efter skadan har mycket av vävnaden redan dött men våra farmakologiska studier visar att hjärnans funktioner ändå kan återfås. Sammanfattningsvis visar avhandlingen på att framtida behandlingsstrategier av stroke bör fokusera på stimulans av hjärnans plasticitet (?formbarhet?) under tiden efter skadan. En utökad förståelse av den kritiska perioden för plasticitet och funktionell återhämtning kommer ha avgörande betydelse för utgången av framtida kliniska studier. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Koistinaho, Jari, Kuopio University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicin (människa och djur), Medicine (human and vertebrates), apolipoprotein D, regeneration, brain ischemia, functional recovery
pages
165 pages
publisher
Laboratory for Experimental Brain Research
defense location
Wallenberg Neuroscience Center Segerfalk lecture hall Lund University
defense date
2007-02-24 09:00:00
ISBN
978-91-85559-05-3
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Laboratory for Experimental Brain Research (013041000)
id
c0398371-b271-45a9-b63a-331be11be569 (old id 548043)
date added to LUP
2016-04-01 16:55:27
date last changed
2018-11-21 20:45:15
@phdthesis{c0398371-b271-45a9-b63a-331be11be569,
  abstract     = {{Stroke is the most common life-threatening neurological disease and ranks as the third leading cause of death in major industrialized countries. It is also the leading cause of serious long-term disability and about sixty percent of survivors have disabilities in their extremities. Recovery of certain neurological functions occurs over time, which has been attributed to endogenous restorative processes in areas adjacent and remote from the infarct area. The area adjacent to infarct, the peri-infarct area, shows activation of processes pertinent for recovery such as enhanced cellular excitability and axonal sprouting. The major objective of this thesis has been to unravel some aspects of functional recovery following stroke. In Paper I, we undertook a comprehensive investigation of gene expression changes in the peri-infarct area during the first 24 h after insult using large-scale array technology. Several genes associated with tissue regeneration and recovery, were activated early after the ischemic insult. In particular, we identified genes related to lipid transport and myelin formation as well as genes involved in synaptic plasticity. This suggests that parallel to cell death signaling and ensuing cell death in severely injured areas, repair processes are induced in the adjacent surviving areas. In Paper II and II, we characterized expression of transcriptional regulators/effectors most likely implicated in adaptation/stress response of the peri-infarct area.<br/><br>
<br/><br>
The second part of the thesis focused on the long-term recovery period (0-30 days) following stroke. In Paper IV, we investigated the role of Apolipoprotein D, a transport protein known to be important for lipid trafficking. ApoD accumulated along the rim of the infarct during the first week of recovery and was localized to oligodendrocytes. We believe that this expression is associated with regeneration of the peri-infarct area and ApoD may function as a lipid carrier providing myelinating oligodendrocytes with cholesterol for axonal regeneration. Further, housing animals in an enriched setting during the post-ischemic period elicited increased levels of ApoD and this was associated with an improved functional recovery. In Paper V, we showed that administration of a receptor ligand, initiated two days following insult, enhanced functional recovery. The mechanisms of this recovery enhancing effects were attributed to stimulation of axonal outgrowth and possibly regulation of lipid transport in the peri-infarct area. The last two studies reveal novel aspects of recovery by emphasizing the importance of lipid trafficking for formation of new connections of the brain.<br/><br>
<br/><br>
Overall, this thesis shows that the injured brain activates repair processes early after an ischemic insult and that these events can be stimulated by either pharmacology and/or enriched environment. Delaying commencement of pharmacological treatment for days after injury still results in an improvement in functional outcome. This finding together with other reports strongly argue that the therapeutic time window after stroke is much more extensive than previously believed. Eligible future stroke therapies must consider beyond the acute phase of cell death and focus on enhancement of post-injury plasticity.}},
  author       = {{Rickhag, Mattias}},
  isbn         = {{978-91-85559-05-3}},
  keywords     = {{Medicin (människa och djur); Medicine (human and vertebrates); apolipoprotein D; regeneration; brain ischemia; functional recovery}},
  language     = {{eng}},
  publisher    = {{Laboratory for Experimental Brain Research}},
  school       = {{Lund University}},
  title        = {{Gene Expression Changes and Brain Plasticity after Experimental Stroke}},
  year         = {{2007}},
}