Animal Models of Stroke Are they valuable for discovering neuroprotective agents? Wu Li-ping

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 CompoundMechanism of actiona Inclusion period (h) Outcome (clinical phase) Reason SelfotelNMDA receptor antagonist 6Negative (III)Adverse events CerveneKappa opioid peptide receptor antagonist 6Negative (III)Lack of efficacy LubeluzoleNOS inhibitor and Nat channel blocker 8Negative (III)Lack of efficacy GavestinelAntagonist at the glycine site of the NMDA receptor 6Negative (III)Lack of efficacy EnlimomabAnti-ICAM antibody6Negative (III)Lack of efficacy and adverse events CiticolineCell-membrane stabilizer24Negative (III)Lack of efficacy Ca 2+ antagonistsCa 2+ channel antagonists6-24Negative (meta-analysis)Lack of efficacy AptiganelNMDA receptor antagonist 6Negative (III)Lack of efficacy ClomethiazoleGABAA receptor modulator 12Negative (III)Lack of efficacy BMS204352bKt channel blocker6Negative (III)Lack of efficacy

Animal models of stroke  Global ischaemia  Focal ischaemia  Haemorrhagic

Table 2. Major animal models of stroke Type of modelRepresentative modelsNotes Global ischaemia  Bilateral carotid occlusion  Two-vessel occlusion plus hypotension  Four-vessel occlusion  Primarily in gerbils, rapid screening technique  Normally in rats Focal ischaemiaMiddle 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 HaemorrhagicInfusion of collagenase into brain

Are animal models relevant to the clinical situation?  Reperfusion  Hyperglycemia  Hyperthermia  Blood pressure

Ischemic damage: Reperfusion < Permanent occlusion

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

Are animal models relevant to the clinical situation?  Reperfusion  Hyperglycemia  Hyperthermia  Blood pressure

Hypothermia is beneficial to animal models and patients of stroke

Are animal models relevant to the clinical situation?  Reperfusion  Hyperglycemia  Hyperthermia  Blood pressure

Why have clinical trials failed despite success in animal models?  Drug exposure  Window of opportunity  Appropriate animal model

Drug exposure Adverse events limits the possibility of achieving the effective dose levels Much higher dose of compounds is needed in permanent ischemia

Window of opportunity Animal models: min at Patients: 1-2 h Treatments should be given after stroke (Such as reperfusion and compounds)

Appropriate animal model MCAO model Pre-MCAO Post-MCAO

Further improving information from animal models  Size of histological protection and subcortical protection  White matter protection  Length of treatment  Monotherapy

STAIR recommendations † Adequate dose–response studies and serum concentrations measured to define minimally and maximally effective doses. † Time-window studies to confirm efficacy. † Physiological monitoring should be undertaken. † Randomized, blinded studies that give reproducible effects (one independent). † Infarct volume measured and functional tests used, including short-term and long-term assessment. † Small rodent studied with permanent middle cerebral artery occlusion (MCAO); if only model used is transient MCAO, then reperfusion should be targeted in clinic. † Larger species used for novel, first-in-class compound. † Studies published in peer-reviewed journal.

Additional proposals † Histological protection should be 70% in both transient and permanent focal ischaemia when drug is given 15–30 min post-occlusion † Must show efficacy in models of permanent MCAO † Should provide subcortical and cortical protection † Attenuates damage to white matter in brain † Time and duration of drug administration should be appropriate to the mechanism of action and the proposed clinical protocol † Compound is efficacious as monotherapy

Conclusion Animal models  Having clinical relevance  To be modified

Thank you