Nicotinamide Modulates Energy Utilization and Improves Functional Recovery from Ischemia in the In Vitro Rabbit Retina

Abstract

The central nervous system depends critically on a regular supply of oxygen and glucose for the formation of adenosine triphosphate (ATP) and the sustenance of its energy metabolism. Consequently, a significant reduction in the supply of oxygen and glucose to neuronal tissue causes an imbalance between the energy supply and demand, inducing the onset of neuronal ischemia and triggering many metabolic cascades leading to irreversible injury and cell death. Nicotinamide (NAm), an essential precursor to nicotinamide adenine dinucleotide (NAD+), which raises brain ATP levels, may improve cerebral blood flow and is neuroprotective against ischemia‐induced injury. We therefore chose to examine the metabolic and electrophysiologic/functional effects of NAm (0.1 mM, 1.0 mM, 10.0 mM) under normal, control, and ischemic conditions, as well as following the early stages of reperfusion (“return‐to‐control” conditions) using an in vitro rabbit retina model where blood flow effects are excluded. Under nonischemic, control conditions, the protective concentration of NAm (10.0 mM) increased glucose utilization (34%, P < 0.01) and decreased lactate production (44%, P < 0.01), but had no significant effect on electrophysiologic function. After 2 h of ischemia, glucose utilization was significantly decreased (41%, P < 0.01) and lactate production was unaffected by NAm (10 mM). Following 3 h of “reperfusion”, NAm (10 mM) significantly improved glucose utilization (217%, P < 0.01), lactate production (40%, P < 0.01), and electrophysiologic function (264%, P < 0.01) relative to controls. Thus, the functional neuroprotective effects of NAm may be independent of blood flow effects, but related, at least in part, to its improvement of tissue glucose utilization and lactate production.

Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

“…Following breaks in DNA strands caused by oxidative damage, PARP binds to single or double strand breaks and cleaves NAD to catalyze the transfer of ADP-ribose, which binds to acceptor proteins and to PARP itself reducing amount of free NAD for normal energy metabolism (Virag and Szabo, 2002). Chronic PARP activation quickly depletes cellular NAD stores, administration of NAM has been shown to inhibit PARP, increase levels of NAD in cortical areas affected by ischemic events, and restore ATP levels (Chang et al, 2002, Sadanaga-Akiyoshi et al, 2003, Tam et al, 2005. NAM has also been shown to prevent cellular injury, due to inflammation, by maintaining membrane asymmetry and inhibiting several cytokines (Li et al, 2006).…”

Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

“…Although this concentration was higher than the usual VIP doses tested for neuroprotection [34], our previous studies using VIP with the presence of aMSC support the use of 5 μM concentration in the study presented here. On the other hand, the NIC concentration (10 mM) has demonstrated neuroprotective properties both in the culture of cortical cells [35] and over ischemic rabbit retina [36]. As well as VIP, our previous studies confirmed the neuroprotective effect of NIC at the mentioned concentration with the presence of aMSC [14].…”

Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus

“…Nicotinamide can limit peripheral nerve injury during elevated glucose, 297 reverse type 1 DM in mice with acetyl‐l‐carnitine, 298 and block oxidant stress 242 , 250 , 252 , 264 , 299 . Nicotinamide affects levels of O‐N‐acetylglucosamin(O‐GlcNAc)ylated proteins 300 and can significantly improve glucose utilization and prevent excessive lactate production in ischemic animal models 301 . In clinical conditions, oral nicotinamide administration (1200 mg/m 2 /d) protects β‐cell function and prevents clinical disease in islet‐cell antibody‐positive first‐degree relatives of type 1 DM 302 .…”

“…242,250,252,264,299 Nicotinamide affects levels of O-N-acetylglucosamin(O-GlcNAc)ylated proteins 300 and can significantly improve glucose utilization and prevent excessive lactate production in ischemic animal models. 301 In clinical conditions, oral nicotinamide administration (1200 mg/m 2 /d) protects β-cell function and prevents clinical disease in isletcell antibody-positive first-degree relatives of type 1 DM. 302 Nicotinamide administration (25 mg/kg) has been shown in patients with recent-onset type 1 DM to reduce HbA 1c levels when combined with intensive insulin therapy for up to 2 years after diagnosis.…”