[Thesis]. Manchester, UK: The University of Manchester; 2018.
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
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.