d-jnki-1 and Brain-Injuries

Traumatic brain injury (TBI) is a major environmental risk factor for subsequent development of Alzheimer disease (AD). Pathological features that are common to AD and many tauopathies are neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated tau. Axonal accumulations of total and phospho-tau have been observed within hours to weeks, and intracytoplasmic NFTs have been documented years after severe TBI in humans. We previously reported that controlled cortical impact TBI accelerated tau pathology in young 3xTg-AD mice. Here, we used this TBI mouse model to investigate mechanisms responsible for increased tau phosphorylation and accumulation after brain trauma. We found that TBI resulted in abnormal axonal accumulation of several kinases that phosphorylate tau. Notably, c-Jun N-terminal kinase (JNK) was markedly activated in injured axons and colocalized with phospho-tau. We found that moderate reduction of JNK activity (40%) by a peptide inhibitor, D-JNKi1, was sufficient to reduce total and phospho-tau accumulations in axons of these mice with TBI. Longer-term studies will be required to determine whether reducing acute tau pathology proves beneficial in brain trauma.

Topics: Amyloid beta-Peptides; Animals; Brain Injuries; Cerebral Cortex; Disability Evaluation; Disease Models, Animal; Enzyme Inhibitors; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Transgenic; Nerve Tissue Proteins; Peptides; Phosphorylation; Presenilin-1; Severity of Illness Index; tau Proteins; Tauopathies

N-methyl-D-aspartate (NMDA)-induced pial artery dilation (PAD) is reversed to vasoconstriction after fluid percussion brain injury (FPI). Tissue type plasminogen activator (tPA) is up-regulated and the tPA antagonist, EEIIMD, prevents impaired NMDA PAD after FPI. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is also up-regulated after traumatic brain injury (TBI). We hypothesize that tPA impairs NMDA-induced cerebrovasodilation after FPI in a MAPK isoform-dependent mechanism.. Lateral FPI was induced in newborn pigs. The closed cranial window technique was used to measure pial artery diameter and to collect cerebrospinal fluid (CSF). ERK, p38, and JNK MAPK concentrations in CSF were quantified by ELISA.. CSF JNK MAPK was increased by FPI, increased further by tPA, but blocked by JNK antagonists SP600125 and D-JNKI1. FPI modestly increased p38 and ERK isoforms of MAPK. NMDA-induced PAD was reversed to vasoconstriction after FPI, whereas dilator responses to papaverine were unchanged. tPA, in post-FPI CSF concentration, potentiated NMDA-induced vasoconstriction while papaverine dilation was unchanged. SP 600125 and D-JNKI1, blocked NMDA-induced vasoconstriction and fully restored PAD. The ERK antagonist U 0126 partially restored NMDA-induced PAD, while the p38 inhibitor SB203580 aggravated NMDA-induced vasoconstriction observed in the presence of tPA after FPI.. These data indicate that tPA contributes to impairment of NMDA-mediated cerebrovasodilation after FPI through JNK, while p38 may be protective. These data suggest that inhibition of the endogenous plasminogen activator system and JNK may improve cerebral hemodynamic outcome post-TBI.

Topics: Animals; Animals, Newborn; Anthracenes; Brain Injuries; Butadienes; Drug Interactions; Female; Imidazoles; JNK Mitogen-Activated Protein Kinases; Male; Mitogen-Activated Protein Kinases; N-Methylaspartate; Nitriles; Oligopeptides; Papaverine; Peptides; Pia Mater; Pyridines; Swine; Tissue Plasminogen Activator; Up-Regulation; Vasoconstriction; Vasodilation