Animal Models of Stroke ------Are they valuable for discovering neuroprotective agents? Wu Li-ping 2005-04-22
Animal Models of Stroke ------Are they valuable for discovering neuroprotective agents? Wu Li-ping 2005-04-22
Ischaemic Haemorrhagic . Common carotid arten TRENDS M Pharmaoological Sciences
Therapy of stroke >1.Reperfusion >2.Neuroprotective agents
Therapy of stroke ➢ 1. Reperfusion ➢ 2. Neuroprotective agents
Table 1.Compounds that have failed recently in clinical evaluation for the treatment of acute ischaemic stroke Compound Mechanismof Inclusion Outcome(clinical Reason actiona period(h) phase) meoepa 6 Negative(ll) Cervene Negative(l) Lack of efficacy Lubeluzole Negative(ll) Lack of efficacy Gavestinel 6 Negative(l) Lack of efficacy of the NMDA receptor Enlimomab Anti-CAM antibody 6 Negative(ll) Lack of efficacy and adverse events Citicoline Cell-membrane stabilizer 24 Negative(lll) Lack of efficacy Ca2antagonists Ca2+channel antagonists 6-24 Negative(meta-analysis) Lack of efficacy Aptiganel NMDA receptor 6 Negative(l) Lack of efficacy Clomethiazole Negative() Lack of efficacy BMS204352b Kt channel blocke Negative ( ack of efficacy
Table 1. Compounds that have failed recently in clinical evaluation for the treatment of acute ischaemic stroke Compound Mechanism of actiona Inclusion period (h) Outcome (clinical phase) Reason Selfotel NMDA receptor antagonist 6 Negative (III) Adverse events Cervene Kappa opioid peptide receptor antagonist 6 Negative (III) Lack of efficacy Lubeluzole NOS inhibitor and Nat channel blocker 8 Negative (III) Lack of efficacy Gavestinel Antagonist at the glycine site of the NMDA receptor 6 Negative (III) Lack of efficacy Enlimomab Anti-ICAM antibody 6 Negative (III) Lack of efficacy and adverse events Citicoline Cell-membrane stabilizer 24 Negative (III) Lack of efficacy Ca2+ antagonists Ca2+ channel antagonists 6-24 Negative (meta-analysis) Lack of efficacy Aptiganel NMDA receptor antagonist 6 Negative (III) Lack of efficacy Clomethiazole GABAA receptor modulator 12 Negative (III) Lack of efficacy BMS204352b Kt channel blocker 6 Negative (III) Lack of efficacy
Animal models of stroke > Global ischaemia Focal ischaemia >Haemorrhagic
Animal models of stroke ➢ Global ischaemia ➢ Focal ischaemia ➢ Haemorrhagic
Table 2.Major animal models of stroke Type of model Representative models Notes Global ischaemia Bilateral carotid occlusion Primarily in gerbils,rapid screening technique -Two-vessel occlusion plus hypotension Normally in rats Four-vessel occlusion Normally in rats Focal ischaemia Middle cerebral artery occlusion: (1)uses clips,intraluminal thread and snare (1)transient (2)uses intraluminal thread,clips and coagulation (2)Permanent (3)injection of either microspheres or clots into (3)Thrombotic cerebral vessels,including middle cerebral artery Haemorrhagic Infusion of collagenase into brain
Table 2. Major animal models of stroke Type of model Representative models Notes Global ischaemia Bilateral carotid occlusion Two-vessel occlusion plus hypotension Four-vessel occlusion Primarily in gerbils, rapid screening technique Normally in rats Normally in rats Focal ischaemia Middle cerebral artery occlusion: (1) transient (2) Permanent (3) Thrombotic (1) uses clips, intraluminal thread and snare (2) uses intraluminal thread, clips and coagulation (3) injection of either microspheres or clots into cerebral vessels, including middle cerebral artery Haemorrhagic Infusion of collagenase into brain
Are animal models relevant to the clinical situation? Reperfusion Hyperglycemia Hyperthermia
Are animal models relevant to the clinical situation? ➢ Reperfusion ➢ Hyperglycemia ➢ Hyperthermia ➢ Blood pressure
Ischemic damage: Reperfusion Permanent occlusion 150 100 50 Control 1.5 3.0 4.5 MCAO Time of onset of reperfusion thrombolysis(h) (2h)
Ischemic damage: Reperfusion < Permanent occlusion
Are animal models relevant to the clinical situation? Reperfusion Hyperglycemia Hyperthermia
Are animal models relevant to the clinical situation? ➢ Reperfusion ➢ Hyperglycemia ➢ Hyperthermia ➢ Blood pressure
A worse outcome with hyperglycemia To reperfused,but not non-reperfused patients or animals
A worse outcome with hyperglycemia To reperfused, but not non-reperfused patients or animals