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J. Badaut1,2, D. Ajao2, J Kamper3, V Pop1, S Ahswal1, R Hartman3, A Obenaus1,4,5,6

Departments of 1Pediatrics, 2Physiology, 3Psychology, 4Radiation Medicine, 5Biophysics & Bioengineering, and 6Radiology

Inhibition of the JNK pathway improves the longInhibition of the JNK pathway improves the long--term term

functional recovery after juvenilefunctional recovery after juvenile

traumatic brain injurytraumatic brain injury

NIH RO1 HD061946

JNK-

signalosomes:

1) JNK1, JNK2

ubiquitous and JNK 3

in Heart, Brain and

testis

2) the outcome of JNK

signaling depends of

several factors

Adapted from Waetzig & Herdegen, TIPS Vol. 26, 2005

Apoptosis

Regeneration

JNK in TBI: Contradictory resultsModel of TBI JNK

activationJNK

inhibitorReferences

FPI n.a. Raghupathi et al., 2003

FPI n.a. Otani et al. 2002

Role of JNK in Juvenile TBI?

CCI SB203580 Mori et al., 2002

Human TBI n.a. Ortolano et al., 2009

CCI PeptideD-JNKI

Ortolano et al., 2009

JNK is potentially activated in juvenile TBI

and

DJNKI is a potential therapeuticaldrug in Juvenile TBI

JNK

JIP

P P

Activation of JNK

P

+

PP

JNK

SubstrateSubstrate

Phosphorylation

D-JNKI: Inhibitor Peptide acting on JNK binding domain

1)

S S

JNK

JIP No access of JNK to JIP or substrate

Adapted from Waetzig & Herdegen, TIPS Vol. 26, 2005Adapted from Borsello & Bonny Trends Mol. Med. Vol10, 2004

TAT Peptide acting on JBDForm LL-JNKI

D-JNKITATPeptide acting on JBDForm D

2)

S

Experimental protocol

JuvenileTBI: CCI in Rat-P17

Ajao et al., 2011, submitted

sham

3d-TBI

NeuN-GFAP

Does D-JNKI improve motor functions ?

D-JNKI improves motor ability: Rotarod

*

*

*

Increased time on rotarod for D-JNKI treatedrats at 7 and 60 days

**

D-JNKI improves motor ability: Foot-faults

*

Decreased number of foot faults for D-JNKI treated rats after 3 days

**

D-JNKI improves motor ability: Turn Bias

**

*

Reduced asymmetry of movement in D-JNKI treated rats at 30 and 60 days

Counting of left and right turns on swim path

**

Does D-JNKI improve behavioral outcomes?outcomes?

D-JNKI decreases anxiety: Zero Maze

**

*

*

D-JNKI treated rats spent less time in the dark arms at 60 days

*

D-JNKI improves spatial learning: MWM

30d 60d** *

Block 1 Block 5

Reduced cumulative distance in D-JNKI treated rats

*

*

*

***

*

*

D-JNKI improves spatial memory: MWM Probe test

*

Saline

*

*

Increased number of entries to platform in D-JNKI-treated rats

D-JNKI

Does D-JNKI improve lesion volume over time?over time?

D-JNKI reduces lesion volume

T2-WI

Saline

T2-WI

DJNKI

Summary & PerspectivesSummary & Perspectives

�IP injection of D-JNKI 3h after jTBI:�Improved motor functions�Reduced development of Anxiety�Improved spatial learning�Improved spatial memory�Improved spatial memory�Decreased the lesion volume

�Molecular and cellular changes sustaining behavioral improvements?