Journal of neurochemistry
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Journal of neurochemistry · Feb 2013
15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) protects neurons from oxidative death via an Nrf2 astrocyte-specific mechanism independent of PPARγ.
Astrocytes are critical for the antioxidant support of neurons. Recently, we demonstrated that low level hydrogen peroxide (H(2) O(2) ) facilitates astrocyte-dependent neuroprotection independent of the antioxidant transcription factor Nrf2, leaving the identity of the endogenous astrocytic Nrf2 activator to question. In this study, we show that an endogenous electrophile, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), non-cell autonomously protects neurons from death induced by depletion of the major antioxidant glutathione. ⋯ In addition, several PPARγ agonists of the thiazolidinedione (TZD) family failed to induce neuroprotection. Unexpectedly, however, the TZD troglitazone (which contains a chromanol moiety found on vitamin E) induced astrocyte-mediated neuroprotection, an effect which was mimicked by the vitamin E analogs alpha-tocopherol or alpha-tocotrienol. Our findings lead to two important conclusions: (i) 15d-PGJ2 induces astrocyte-mediated neuroprotection via an Nrf2 but not PPARγ mediated pathway, suggesting that 15d-PGJ2 is a candidate endogenous modulator of Nrf2 protective pathways in astrocytes; (ii) selective astrocyte treatment with analogs or compounds containing the chromanol moiety of vitamin E facilitates non-cell autonomous neuroprotection.
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Journal of neurochemistry · Dec 2012
Mitogen- and stress-activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus.
The neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus is a source of new neurons throughout life. Interestingly, SGZ proliferative capacity is regulated by both physiological and pathophysiological conditions. One outstanding question involves the molecular mechanisms that regulate both basal and inducible adult neurogenesis. ⋯ This blunting of cell proliferation in MSK1/2 null mice was partially reversed by forskolin infusion, indicating that the inducible proliferative capacity of the progenitor cell population was intact. Furthermore, in MSK1/2 null mice, DCX-positive immature neurons exhibited reduced neurite arborization. Together, these data reveal a critical role for MSK1/2 as regulators of both basal and activity-dependent progenitor cell proliferation and morphological maturation in the SGZ.
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Journal of neurochemistry · Nov 2012
ReviewTransition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage.
Subarachnoid hemorrhage is a devastating disease that can be difficult to manage. Not only is the initial bleeding and rebleeding associated with high mortality, but a large fraction of patients also develop a delayed neurological deficit even when the aneurysm was successfully secured with clipping or coiling. Past research effort has traditionally been focused on vasospasm, which was conceived to be the sole factor for delayed neurological deficit. ⋯ Focusing only on the treatment of vasospasm with complete disregard for early brain injury is insufficient for the management of subarachnoid hemorrhage. Instead, a therapeutic intervention has to aim at stopping the molecular cascades of early brain injury that may lead to long-term deficits in addition to vasospasm. We review the pathological mechanisms of early brain injury, which may reveal new therapeutic avenues that can be exploited to serve as combination therapy with anti-vasospasm medications in the future.
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Journal of neurochemistry · Nov 2012
Retracted PublicationEthanol disrupts axon outgrowth stimulated by netrin-1, GDNF, and L1 by blocking their convergent activation of Src family kinase signaling.
Pre-natal alcohol exposure causes fetal alcohol spectrum disorders (FASD), the most common, preventable cause of developmental disability. The developing cerebellum is particularly vulnerable to the effects of ethanol. We reported that ethanol inhibits the stimulation of axon outgrowth in cerebellar granule neurons (CGN) by NAP, an active motif of activity-dependent neuroprotective protein (ADNP), by blocking NAP activation of Fyn kinase and its downstream signaling molecule, the scaffolding protein Cas. ⋯ Clinically relevant concentrations of ethanol inhibited axon outgrowth and the activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, and L1, but did not disrupt BDNF-induced axon outgrowth or ERK1/2 activation. These results indicate that SFK, but not ERK1/2, is a primary target for ethanol inhibition of axon outgrowth. The ability of ethanol to block the convergent activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, L1, and ADNP could contribute significantly to the pathogenesis of FASD.
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Journal of neurochemistry · Oct 2012
Neuron-specific non-classical release of prothymosin alpha: a novel neuroprotective damage-associated molecular patterns.
Prothymosin alpha (ProTα), 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 ProTα 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 ProTα under cerebral ischemia is yet unknown. ⋯ Interestingly, Z-Val-Ala-Asp fluoromethyl ketone, a caspase 3 inhibitor, pre-treatment induces ProTα 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 ProTα distribution in microglia upon cerebral ischemia. Taken together, these results suggest that only neurons have machineries to release ProTα upon cerebral ischemic stress in vivo.