Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

Chemotherapy-induced peripheral neuropathy (CIPN),ϩ T cells. In conclusion, we identified a novel mechanism for resolution of CIPN that requires CD8 ϩ T cells and endogenous IL-10. We propose that CD8 ϩ T cells increase DRG IL-10 receptor expression and that IL-10 suppresses the abnormal paclitaxel-induced spontaneous discharges by DRG neurons to promote recovery from CIPN.

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration–approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin–dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.