Response to Letter by Tsuda
Dr Tsuda raised the interesting speculation that production of nitric oxide (NO) might play a role in the neuroprotective effect of leptin against ischemic neuronal injury. Although our study did not address this hypothesis,1 we agree that NO generated via the activation of endothelial nitric oxide synthase (eNOS) could potentially contribute to leptin-mediated neuroprotection in the stroke model.
One of the major roles of leptin is to increase energy consumption by augmenting sympathetic outflow,2 which normally would increase blood pressure. However, blood pressure is not increased after the administration of leptin, presumably because of its ability to induce endothelial production of NO via eNOS,3,4 resulting in dilation of blood vessels in opposition to the sympathetic vasoconstriction effects. Interestingly, a neuroprotective role of NO released by eNOS has been demonstrated previously, because eNOS knockout mice show larger cerebral infarcts than wild-type animals after brain ischemia.5 The greater susceptibility to ischemic damage in the eNOS knockout animals was related to a marked reduction in regional cerebral blood flow (CBF) after ischemic insult.5 Our study did not find any gross changes in CBF as measured using laser-Doppler flowmetry, although very small changes may be below the detection limits of the technique. Thus, we cannot completely rule out the eNOS/NO/CBF mechanism as a contributing factor in leptin-mediated neuroprotection in the stroke model. An interesting future study would be to examine the effect of leptin treatment against brain ischemia in the eNOS knockout mice.
Recent studies have also suggested that NO could contribute to cytoprotection against cardiac ischemia via activating the NO-cGMP-PKG signaling pathway,6,7 which is presumably independent of the vascular effect of eNOS-generated NO. Nevertheless, our experiments identified extracellular signal-regulated kinase (ERK) 1/2 as the predominant signaling mechanism that mediates leptin neuroprotection in both in vitro and in vivo models of brain ischemia. Whether the NO-cGMP-PKG signaling pathway plays a cytoprotective role in ischemic neurons or contributes to leptin neuroprotection by cross-talking with the ERK1/2 pathway remains to be understood.
Collectively, leptin may confer neuroprotection against ischemic brain injury via potentially 2 distinct mechanisms by acting on the eNOS-dependent cerebral blood flow regulation and directly by activating neuroprotective intracellular signaling cascades. The possibility of a dual neuroprotective mechanism may be an advantage of leptin and lends support for further investigation into leptin as a tool for the treatment of ischemic injury.
Zhang F, Wang S, Signore AP, Chen J. Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke. 2007; 38: 2329–2336.
Das A, Smolenski A, Lohmann SM, Kukreja RC. Cyclic GMP-dependent protein kinase iα attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocytes. J Biol Chem. 2006; 281: 38644–38652.
Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res. 2005; 97: 329–336.