Neuron‐specific non‐classical release of prothymosin alpha: a novel neuroprotective damage‐associated molecular patterns

Prothymosin alpha ( P ro T α), a nuclear protein devoid of signal sequence, has been shown to possess a number of cellular functions including cell survival. Most recently, we demonstrated that P ro T α is localized in the nuclei of neurons, while it is found in both nuclei and cytoplasm in the astrocytes and microglia of adult brain. However, the cell type‐specific non‐classical release of P ro T α under cerebral ischemia is yet unknown. In this study, we report that P ro T α is non‐classically released along with S100A13 from neurons in the hippocampus, striatum and somatosensory cortex at 3 h after cerebral ischemia, but amlexanox (an anti‐allergic compound) reversibly blocks this neuronal P ro T α release. We found that none of P ro T α is released from astrocytes and microglia under ischemic stress. Indeed, P ro T α intensity is increased gradually in astrocytes and microglia through 24 h after the cerebral ischemia. Interestingly, Z‐Val‐Ala‐Asp fluoromethyl ketone, a caspase 3 inhibitor, pre‐treatment induces P ro T α release from astrocytes in the ischemic brain, but this release is reversibly blocked by amlexanox. However, Z‐Val‐Ala‐Asp fluoromethyl ketone as well as amlexanox has no effect on P ro T α distribution in microglia upon cerebral ischemia. Taken together, these results suggest that only neurons have machineries to release P ro T α upon cerebral ischemic stress in vivo .