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<\/p>\nReplenishment of NAD+\u00a0has 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+\u00a0in 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\u2009minutes 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.<\/p>\n
Intracerebral hemorrhage (ICH) is a devastating type of stroke occurring when an abnormal blood vessel within the brain disrupts, allowing blood to leak inside the brain tissue. Although hemorrhagic strokes are less common, accounting less than 15% of all strokes cases, they are responsible for about half of all stroke deaths, and is associated with worse recovery than ischemic stroke both in world. The primary brain injury induced by ICH, which is always considered to be hematoma-caused mechanical damage, takes place within several minutes to hours after the onset of bleeding. Secondary injury is resulted by the subsequent pathophysiological changes and the complex interaction between them. These pathophysiological changes following ICH include, but are not limited to, blood-brain barrier breakdown, hemoglobin-induced iron overload, excitotoxicity, neuroinflammation activation, triggered oxidative stress and neural cell death\/apoptosis. Currently, large scale clinical trials have not reached a consensus on the benefit of surgical evacuation in treatment of ICH-induced primary injury. Thus, targeting the secondary injury attracts great attentions for development of novel therapeutic strategies for ICH.<\/p>\n
NAD+\u00a0is a well-known ubiquitous pyridine nucleotide that functions as an essential cofactor in mitochondrial oxidative phosphorylation. Classically, NAD+\u00a0is considered to be just a coenzyme which is essential for mitochondrial electron transfer chain. However, overwhelming evidence in recent years has demonstrated that NAD+\u00a0not only acts as a coenzyme, but also participates in the transduction of numerous important intracellular signaling pathways to critically regulate numerous biological functions including cell death, metabolism, circadian rhythms, aging and immunity through regulating several NAD+-consuming proteins such as sirtuin family proteins and poly(ADP-ribose) polymerases. As NAD+\u00a0depletion is a necessary event for neuronal death, supplement of NAD+\u00a0is neuroprotective through enhancing NAD+\u00a0pool. Our group has provided numerous evidence of the neuroprotection of NAD+\u00a0. Nicotinamide mononucleotide (NMN) is a particularly interesting chemical compound used to replenish NAD+. NMN is a key intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis from nicotinamide, which is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT) in mammals. Recent evidence suggests that NMN treats obesity, vascular aging\u00a0and islet damage. Besides, NMN has favorable effects in central nerve system (CNS) by raising brain mitochondrial respiratory deficits, protecting \u03b2-amyloid oligomer-induced cognitive impairment, delaying astrocyte-mediated motor neuron death\u00a0and maintaining neural stem\/progenitor cells. We and other group also previously demonstrated that NMN protectes against cerebral ischemia-induced neural apoptosis and promotes neurogenesis after cerebral ischemia. The potential therapeutic values of NMN in cerebral ischemic stroke have been discussed in detail in our previous review. However, the effects of NMN in hemorrhagic stroke have not been examined yet.<\/p>\n
In the present study, we conducted a straightforward study to determine whether replenishment of NAD+\u00a0by NMN, the key intermediate of NAD+\u00a0biosynthesis, is able to enhance intracerebral NAD+\u00a0pool and treat ICH-induced brain injury in animal model and, if so, to further explore the molecular mechanisms underlying the therapeutic action of NMN in ICH.<\/p>\n
Hematoma volume, brain hemoglobin content, body weight, brain water content and neurological function deficit were evaluated at 24\u2009h after cICH. A single dose of NMN treatment given at 30\u2009minutes (i.v.) post cICH increased intracerebral NAD+\u00a0concentrations at 2 and 6\u2009hours post cICH (\u00a0At 12 and 24\u2009hours later, the NAD+\u00a0level returned to basal . NMN treatment did not affect the hematoma volume , decline of body weight and brain hemoglobin content . Interestingly, the induction of edema in striatum (water content) by cICH was slightly but significantly reduced by NMN treatment. Beam walking test demonstrated that NMN improved the neurological function at 24\u2009hours after cICH . These data suggest that NMN is unable to reduce hematoma volume, but it alleviates ICH-induced brain injury.<\/p>\n
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Nicotinamide mononucleotide (NMN) treatment protects against cICH-induced brain injury. (A<\/b><\/strong>) NAD+\u00a0level in brain tissue was measured at 2\u2009hours after injection of NMN from tail vein. *P\u2009<\u20090.05 vs Vehicle; NS, no significance. N\u2009=\u20096 per group. (B<\/b><\/strong>) Brain hematoma volume at 24\u2009hours after cICH. n\u2009=\u20098 per group. (C<\/b><\/strong>) Body weight at 24\u2009hours after cICH. ***P<\/i><\/em>\u2009<\u20090.001 vs Sham, n\u2009=\u200922, 60 and 63 in Sham, cICH\u2009+\u2009Vehicle and cICH\u2009+\u2009NMN groups respectively. (D<\/b><\/strong>) Hemoglobin content at 24\u2009hours after cICH. n\u2009=\u20098 per group. (E<\/b><\/strong>) Brain water content at 24\u2009hours after cICH in cortex and striatum. **P<\/i><\/em>\u2009<\u20090.01 cICH\u2009+\u2009Vehicle vs Sham, *P<\/i><\/em>\u2009<\u20090.05 cICH\u2009+\u2009NMN vs cICH\u2009+\u2009Vehicle, n\u2009=\u20098. (F<\/b><\/strong>) Neurological deficit was evaluated by beam walking test at 24\u2009hours after cICH. **P<\/i><\/em>\u2009<\u20090.01, n\u2009=\u200926, 69 and 73 in Sham, cICH\u2009+\u2009Vehicle and cICH\u2009+\u2009NMN groups respectively. NS, no significance.<\/p>\n Auther:Chun-Chun Wei,\u00a0Yuan-Yuan Kong,\u00a0Guo-Qiang Li,\u00a0Yun-Feng Guan,\u00a0Pei Wang\u00a0&\u00a0Chao-Yu Miao<\/p>\n This article is reprinted from\u00a0Nature.com<\/a>\u00a0without changed under the Creative Commons license, original article please see\u00a0https:\/\/www.nature.com\/articles\/s41598-017-00851-z#Fig1<\/a> Replenishment of NAD+\u00a0has 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+\u00a0in ICH. In a collagenase-induced ICH (cICH) mouse model, nicotinamide mononucleotide (NMN), a key intermediate […]<\/p>\n","protected":false},"author":1,"featured_media":70,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[14,6],"class_list":["post-69","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-nmn","tag-brain-health","tag-nmn"],"_links":{"self":[{"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/posts\/69","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=69"}],"version-history":[{"count":2,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/posts\/69\/revisions"}],"predecessor-version":[{"id":95,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/posts\/69\/revisions\/95"}],"wp:featuredmedia":[{"embeddable":true,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=\/wp\/v2\/media\/70"}],"wp:attachment":[{"href":"http:\/\/johnhealth.blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=69"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=69"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/johnhealth.blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=69"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
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