Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway

Abstract

Replenishment of NAD+ has been shown to protect against brain disorders such as amyotrophic lateral sclerosis and ischemic stroke. However, whether this intervention has therapeutic effects in intracerebral hemorrhage (ICH) is unknown. In this study, we sought to determine the potential therapeutic value of replenishment of NAD+ in ICH. In a collagenase-induced ICH (cICH) mouse model, nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis, was administrated at 30 minutes post cICH from tail vein to replenish NAD+. NMN treatment did not decrease hematoma volume and hemoglobin content. However, NMN treatment significantly reduced brain edema, brain cell death, oxidative stress, neuroinflammation, intercellular adhesion molecule-1 expression, microglia activation and neutrophil infiltration in brain hemorrhagic area. Mechanistically, NMN enhanced the expression of two cytoprotective proteins: heme oxygenase 1 (HO-1) and nuclear factor-like 2 (Nrf2). Moreover, NMN increased the nuclear translocation of Nrf2 for its activation. Finally, a prolonged NMN treatment for 7 days markedly promoted the recovery of body weight and neurological function. These results demonstrate that NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress. The activation of Nrf2/HO-1 signaling pathway may contribute to the neuroprotection of NMN in ICH.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

“…This is supported by recent in vivo work in zebrafish larvae and mice showing that expression of a bacterial NMN-deamidase, which consumes NAD but does not have NAD synthesis activity, rescues axonal defects and promotes axon survival (Di Stefano et al, 2017). On the other hand, NMN preserves hippocampus-dependent spatial memory after forebrain ischemia (Park et al, 2016) and reduces edema, oxidative stress, inflammation, and neuronal death in a mouse collagenase-induced intracerebral hemorrhage (cICH) model (Wei et al, 2017b). …”

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

“…16 Moreover, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), NAD+ precursors, have beneficial effects in neurological degenerative diseases and cardiovascular diseases, such as Parkinson's disease (PD), AD, aging, stroke, and hypertension. [17][18][19][20][21][22][23] However, the administration of the NAD+ precursors maintains the integrity of BBB, reverses endothelial dysfunction, and improves cognitive function and healthspan. 18,23,24 The role of NR in CSVD has not been investigated.…”

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

“…Interestingly, NAD + decline during aging, due to reduced de novo synthesis, impairs phagocytosis and the resolution of inflammation in macrophages, suggesting this could be another potential mechanism by which NAD + precursors reduce neuroinflammation in AD models [89]. Likewise, supplementation with NMN decreased microglia activation, neutrophil infiltration and TNF-α and IL-6 levels in mouse models of intracerebral hemorrhage [90]. NAD + supplementation also efficiently worked in mouse models of EAE, in which it blocks disease progression by regulating T cell differentiation through the activation of the tryptophan hydroxylase-1 (Tph1).…”