Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage

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.

Functions of lactate in the brain of rat with intracerebral hemorrhage evaluated with MRI/MRS and in vitro approaches

“…Lactate accumulation was associated with intracerebral hemorrhage, and it has been verified with the in vivo MRS method. However, there are only a few studies that discuss the function of lactate accumulation 12 . Lactate accumulation has been verified as contributing to angiogenesis and neurogenesis in ICH model, 12 which could interpret partial self‐healing after hemorrhages, especially in the penumbra area.…”

“…However, there are only a few studies that discuss the function of lactate accumulation 12 . Lactate accumulation has been verified as contributing to angiogenesis and neurogenesis in ICH model, 12 which could interpret partial self‐healing after hemorrhages, especially in the penumbra area. Furthermore, we hypothesized that lactate accumulation could facilitate the migration and proliferation of the microglia cell.…”

“…Furthermore, lactate accumulation is also linked to ICH. In recent studies, it also contributed to the potentiating of angiogenesis and neurogenesis 12 . However, the measurement of lactate concentration in these studies was inappropriate due to its dramatic increase after euthanasia of the animal test subject.…”

White matter repair and treatment strategy after intracerebral hemorrhage

“…In the rat model of ICH induced by a collagenase injection, new neurons migrated from the SVZ to the lesion, increasing the regeneration of nerves in the white matter. In addition, an exogenous lactic acid injection after ICH increased the transcription of VEGF and basic fibroblast growth factor (BFGF) through the translocation of nuclear factor‐kappa B (NF‐kappa B), which plays an active role in angiogenesis and neurogenesis . Otero L et al showed that ICH induced strong endogenous neurogenesis within 72 hours to 7 days after injury, but most of the new cells survived less than 3 weeks due to apoptotic‐mediated apoptosis .…”

“…(NF-kappa B), which plays an active role in angiogenesis and neurogenesis. 61 Otero L et al showed that ICH induced strong endogenous neurogenesis within 72 hours to 7 days after injury, but most of the new cells survived less than 3 weeks due to apoptotic-mediated apoptosis. 62 In addition, neurogenesis continued in a small range for at least 1 year after ICH, which provides us with a novel view that promoting endogenous nerve regeneration can improve the prognosis of patients with hemorrhagic stroke.…”