Ischaemic stroke is the fourth leading cause of death in the UK, and is a major cause of disability worldwide. Currently, there is only one licensed drug for the treatment of stroke, known as tissue plasminogen activator (t-PA), which has a very narrow therapeutic window and is only effective in a small number of stroke patients. After an ischaemic stroke, several mechanisms mediating stroke pathophysiology, such as inflammation, are activated. Pre-clinical research is largely focused on limiting these damaging mechanisms, and also promoting repair mechanisms such as restoration of cerebral blood flow (CBF) and angiogenesis. The acute phase protein (PTX3) regulates peripheral inflammation and has also been reported to have a neuroprotective function after epileptic seizures. However, the role of PTX3 in brain inflammation and neuroprotection after cerebral ischaemia is currently completely unknown. Furthermore, PTX3 has been reported to promote repair after cerebral ischaemia, by stimulating BBB repair, reducing oedema, and promoting angiogenesis and neurogenesis. However, the effect of PTX3 on CBF recovery after stroke is currently unknown, and the underlying mechanisms involved in these reparative events remain unclear. Our study found that PTX3 promotes in vitro angiogenic processes, and exerts differential actions depending on the concentration and duration of treatment. Furthermore, we observed a more prominent pro-angiogenic action of PTX3 under hypoxic conditions. Our in vivo studies using the middle cerebral artery occlusion (MCAo) filament model to induce experimental cerebral ischaemia, revealed that PTX3 promotes long-term CBF recovery, angiogenesis, and exerts neuroprotection 28 d after ischaemic stroke. In addition, we assessed the role of PTX3 in neutrophil transmigration through the brain endothelium in vitro, and found that PTX3 regulates neutrophil transmigration. Furthermore, we induced inflammation into the brain via intrastriatal LPS injection or cerebral ischaemia. These studies found that PTX3 reduces neutrophil transmigration to the brain under these inflammatory conditions. In conclusion, our findings suggest that PTX3 may be a useful therapeutic target for ischaemic stroke and possibly other CNS inflammatory disorders, as it promotes repair mechanisms, provides neuroprotection, and prevents damaging inflammatory mechanisms after cerebral ischaemia.
|Date of Award||1 Aug 2018|
- The University of Manchester
|Supervisor||Stuart Allan (Supervisor) & Emmanuel Pinteaux (Supervisor)|