The neuropeptide corticotropin-releasing factor (CRF) is well known to act on the central nervous system in ways that mimic stress and result in decreases in exploration, increases in sympathetic activity, decreases in parasympathetic outflow, and decreases in appetitive behavior. Urocortin, a neuropeptide related to CRF, binds with high affinity to the CRF2 receptor, is more potent than CRF in suppressing appetite, but is less potent than CRF in producing anxiety-like effects and activation. Doses as low as 10 nanograms injected intracerebroventricularly were effective in decreasing food intake in food-deprived and free-feeding rats. These results suggest that urocortin may be an endogenous CRF-like factor in the brain responsible for the effects of stress on appetite.

The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.

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