Inhibition of c-Jun N-Terminal Kinase Protects Against Brain Damage and Improves Learning and Memory After Traumatic Brain Injury in Adult Mice

Abstract

Traumatic brain injury (TBI) is a global risk factor that leads to long-term cognitive impairments. To date, the disease remains without effective therapeutics because of the multifactorial nature of the disease. Here, we demonstrated that activation of the c-Jun N-terminal kinase (JNK) is involved in multiple pathological features of TBI. Therefore, we investigated the disease-modifying therapeutic potential of JNK-specific inhibitor (SP600125) in TBI mice. Treating 2 different models of TBI mice with SP600125 for 7 days dramatically inhibited activated JNK, resulting in marked reductions of amyloid precursor protein (APP) expression level and in amyloid beta production and hyperphosphorylated tau and regulation of the abnormal expression of secretases. Furthermore, SP600125 strongly inhibited inflammatory responses, blood-brain barrier breakdown, apoptotic neurodegeneration, and synaptic protein loss, regulated prosurvival processes and improved motor function and behavioral outcomes in TBI mice. More interestingly, we found that SP600125 treatment ameliorated amyloidogenic APP processing and promoted the nonamyloidogenic pathway in TBI mouse brains. Our findings strongly suggest that active JNK is critically involved in disease development after TBI and that inhibition of JNK with SP600125 is highly efficient for slowing disease progression by reducing multiple pathological features in TBI mouse brains and regulating cognitive dysfunction.

Oral Administration of Alpha Linoleic Acid Rescues Aβ-Induced Glia-Mediated Neuroinflammation and Cognitive Dysfunction in C57BL/6N Mice

“…Immunofluorescence staining was carried out according to standard protocols [39,40]. The slides were dried at room temperature overnight and washed with 0.1 M PBS two times for 10 min.…”

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

“…Follow-up studies revealed that post-injury Aβ and tau pathology could be improved via inhibition of γ-secretase or c-Jun N-terminal kinase (JNK), respectively ( 21 , 190 ). Interestingly, a recent report shows that post-injury JNK inhibition improves amyloid and tau pathology, neuroinflammation, BBB disruption, synaptic loss, and neurodegeneration in non-transgenic mice 7 DPI ( 191 ). Thus, the JNK pathway may be a relevant therapeutic target influencing multiple pathological processes.…”

Stimulation of dopamine D2 receptor via quinpirole protects against brain damage after brain injury in mice

“…While disrupted BBB leads to enhance cytokines infiltration and neuronal susceptibility. Several tight junction proteins are important for the maintenance of BBB integrity, including claudin, occludin and zonula occludin (ZO-1) [51] [22,52]. BBB breakdown in brain injuries is due to marked histopathological brain damage and tissue loss in the affected area [53].…”

“…The stab wound cortical brain injury mouse model was established as previously we described with modification [22,23]. Briefly, the mice were anesthetized with rompun (0.05 mL/100g body weight) and zoletil (0.1 mL/100g body weight) and placed at stereotaxic apparatus, exposed the skull by making a mid-longitudinal incision.…”