Abstract
Subarachnoid hemorrhage (SAH) represents a considerable health problem that strikes patients at a relatively young age. At present, limited options are available to treat the devastating consequences of SAH. The endovascular puncture model is a suitable animal model to study the pathophysiological mechanisms of SAH and to explore potential future therapies. In this thesis, we discuss possible treatment options in the endovascular puncture rat model of SAH. Inflammation and various cell death pathways are shown to be important contributors to cerebral damage after SAH. Neuroprotective treatment strategies aiming at interfering with either inflammation or cell death demonstrate the importance of these mechanisms in the development of brain injury after SAH. In this thesis we propose that targeting molecular pathways, that regulate both inflammation and cell death, will be most effective to combat SAH brain damage. Long-term effects of SAH in the endovascular puncture model were determined at the level of gray and white matter damage, neuroinflammation and behavioral deficits. The acute neurological score was measured daily for 6 days after SAH. Apart from assessing the physical condition, the neurological score at 24 hours post-SAH was especially used to divide the rats into a ‘mild’ and ‘severe’ SAH group. Neuroinflammation was shown to be long-lasting after severe SAH since microglia/macrophages and astrocytes were still abundantly present and activated at 21 days post-SAH. Besides neuroinflammation, long-lasting gray and white matter damage and deficits in sensorimotor behavior were observed at 21 days post-SAH. Importantly, the classification of the animals into ‘mild’ or ‘severe’ SAH is valid since all long-lasting effects of SAH were significantly correlated to the acute neurological score. Limited therapeutical options for SAH patients are available and current options have a short therapeutical time-window. Mesenchymal stem cell (MSC) treatment could be a potential therapeutical option to repair cerebral damage. We demonstrate that intranasal MSC administration at 6 days post-SAH reduced long-term cerebral injury and neuroinflammation. The majority of activated microglia present at 21 days after SAH were polarized towards an anti-inflammatory M2-like phenotype. MSC treatment reduced these M2-like polarized microglia. The decrease in long-term cerebral damage and neuroinflammation after MSC treatment was associated with an improvement in sensorimotor behavior. In addition, SAH reduced the amount of dopamine-expressing neurons in the substantia nigra, which could potentially contribute to decreased motivation associated with depression-like disorders. Depression-like symptoms are frequently observed in SAH patients. Our data clearly showed depression-like behavior in rats undergoing the endovascular puncture model of SAH. Namely, SAH rats showed no preference for drinking sucrose water in the sucrose preference test, a phenomenon that was reversed by the acute anti-depressant ketamine. MSC treatment resulted in an attenuation of depression-like behavior. Our results show that MSC treatment in SAH rats potently reduces cerebral damage, neuroinflammation and depression-like behavior and improves sensorimotor function. Together with the use of a safe administration route and a wide therapeutic window our data highlight MSC treatment as a possible effective therapeutic strategy for SAH in the near future.
Original language | English |
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Qualification | Doctor of Philosophy |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 24 Nov 2014 |
Publisher | |
Print ISBNs | 978-90-393-6221-1 |
Publication status | Published - 24 Nov 2014 |
Keywords
- Econometric and Statistical Methods: General
- Geneeskunde(GENK)
- Medical sciences
- Bescherming en bevordering van de menselijke gezondheid
- Subarachnoid hemorrhage
- Cerebraldamage
- Neuroinflammation
- Sensorimotor behavior
- Depression
- Mesenchymal stem cells