Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage

Jing Zhou,Qing Huang,Jiekun Luo,Ali Yang,En Hu,Pengfei Li,Jun Zhou,Dandan Feng,Tao Tang,Hanjin Cui,Yang Wang,Hao Guo,Tao Liu

doi:10.1038/s12276-018-0113-2

Abstract

Lactate accumulation has been observed in the brain with intracerebral hemorrhage (ICH). However, the outcome of lactate accumulation has not been well characterized. Here, we report that lactate accumulation contributes to angiogenesis and neurogenesis in ICH. In the first set of the experiment, a rat model of ICH was induced by injecting collagenase into the brain. The effects of lactate accumulation on the neurological function, apoptosis, and numbers of newborn endothelial cells and neurons, as well as the proliferation-associated signaling pathway, were evaluated in the rat brain. In the second set, exogenous l-lactate was infused into intact rat brains so that its effects could be further assessed. Following ICH, lactate accumulated around the hematoma; the numbers of PCNA+/vWF+ nuclei and PCNA+/DCX+ cells were significantly increased compared with the numbers in the Sham group. Moreover, ICH induced translocation of nuclear factor-kappa B (NF-κB) p65 into the nucleus, resulting in a notable upregulation of VEGF and bFGF mRNAs and proteins compared with the levels in the Sham controls. Administration of a lactate dehydrogenase inhibitor dramatically inhibited these effects, decreased the vascular density, and aggravated neurological severity scores and apoptosis after ICH. After exogenous l-lactate infusion, the numbers of PCNA+/vWF+ nuclei and PCNA+/DCX+ cells were strikingly increased compared with the numbers in the Sham controls. In addition, lactate facilitated NF-κB translocation to induce increased transcription of VEGF and bFGF. Co-infusion with an NF-κB inhibitor significantly inhibited these effects. These data suggest that lactate potentiates angiogenesis and neurogenesis by activating the NF-κB signaling pathway following ICH.

Highlights

Intracerebral hemorrhage (ICH) is one of the most devastating forms of stroke[1]
Lactate accumulated around the hematoma of ICH The lactate content of perihematomal tissues was significantly increased at days 7 and 14 after ICH (Fig. 1a)
Inhibition of endogenous lactate led to increased brain injury and severe neurological deficits after ICH

Summary

Introduction

12~39% of patients live independently after ICH, and the 30-day mortality of ICH is ~13.1–61%2. Metabolic changes in the brain are clearly a key element of ICH3. Previous studies have indicated that lactate, a metabolic intermediate, accumulates in the brain after ICH4, 5. Lactate was traditionally considered as an indicator of dysfunctional oxidative metabolism for neurons until Schurr et al showed that lactate is able to support synaptic activity[6, 7]. The astrocyteneuron lactate shuttle hypothesis further verifies that lactate can be used by neurons[8]. The neuroprotective effect of lactate has been observed in a mouse model of cerebral ischemia[9]. Lactate administration improves the neurologic outcomes of traumatic brain injury patients[10]

Methods

Results

Conclusion