Phases of Stroke Recovery: Cellular and Molecular Mechanisms

Phases of Stroke Recovery: Cellular and Molecular Mechanisms

S. Thomas Carmichael, M.D., Ph.D. Professor, Vice Chair Depts Neurology and Neurobiology David Geffen School of Medicine at UCLA Co-Director UCLA Broad Stem Cell Center

Cell Death

Normal Progression of Stroke

Inflammation/ Scarring

Improving Impairment/Disability

Process

Treatment

Endogenous Plasticity

Minutes Hours

Thrombolysis/Re canalization

Days

Months

Neuroprotection

Tissue Reorganization

Acute

Subacute

Chronic

Cell Death

Goals of Neural Repair Trials

Inflammation/ Scarring

Improving Impairment/Disability

Minutes Hours

Days

Endogenous Plasticity 3 Months

Two goals in neural repair in stroke: ? Increase the amount or

duration of early plasticity ? Induce greater plasticity late in the disease

>6 Months

Thrombolysis/Re canalization

Neuroprotection

Rehabilitation and Neural Repair

Goal-specific Training and Repair

Acute

Subacute

Chronic

Process

Treatment

Defining the First Phase in Neural Repair: the Death to Repair Transition

Cell Death

Normal Progression of Stroke

Inflammation/ Scarring

Improving Impairment/Disability

Process

Treatment

Minutes Hours Thrombolysis/Re

canalization

Neuroprotection

Acute

Days

Endogenous Plasticity

Months

Tissue Reorganization

Subacute

Chronic

1. Stroke triggers initial hypoxia, excitotoxicity, reperfusion injury and inflammation (in that order)

2. Recovery involves stimulating neuronal circuits, enhancing growth programs and demanding cellular energy

These two 2 processes will exacerbate each other if they overlap

Blocking Tonic GABA Inhibition

Enhancing Glutamate Signaling (AMPAR signaling)

grid

Clarkson et al Nature 468:305; J Neurosci 31:3766

Defining the Second Phase in Neural Repair: Endogenous Plasticity NortmoaCl PhrorgorensiscionSotfaSgtreoke

Cell Death

Inflammation/ Scarring

Improving Impairment/Disability

Process

Treatment

Minutes Hours Thrombolysis/Re

canalization

Neuroprotection

Acute

Days

Endogenous Plasticity

Months

Tissue Reorganization

Subacute

Chronic

Inflection Point (Day 3 in mice)

Tissue sensitivity to excitatory activity

Provokes worsening Cell death

Promotes improved Behavioral recovery

What ends the sensitive period or the Subacute period of substantial recovery?

Acute

Subacute

Chronic

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