Animal Models of Stroke------Are they valuable for discovering

neuroprotective agents?

Wu Li-ping

2005-04-22

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 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

Table 2. Major animal models of strokeType of model Representative models Notes

Global ischaemia Bilateral carotid occlusionTwo-vessel occlusion plus hypotensionFour-vessel occlusion

Primarily in gerbils, rapid screening technique Normally in ratsNormally 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

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 modelsand 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: 60-90 minat

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