Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.
Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.
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DOI：
10.1016/j.redox.2021.101988
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发表时间：
2021-07
期刊：
影响因子：
11.4
通讯作者：
Williams PA
中科院分区：
文献类型：
--
作者：
Tribble JR;Otmani A;Sun S;Ellis SA;Cimaglia G;Vohra R;Jöe M;Lardner E;Venkataraman AP;Domínguez-Vicent A;Kokkali E;Rho S;Jóhannesson G;Burgess RW;Fuerst PG;Brautaset R;Kolko M;Morgan JE;Crowston JG;Votruba M;Williams PA
烟酰胺腺嘌呤二核苷酸（NAD）是神经元存活所必需的氧化还原辅因子和代谢物。青光眼是一种常见的神经退行性疾病，其中神经元NAD水平下降。我们评估了烟酰胺（NAD的前体）在正常生理条件下以及在一系列青光眼相关损伤（包括线粒体应激和轴突变性损伤）中对视网膜神经节细胞（青光眼中受影响的神经元）的影响。我们证明了烟酰胺在啮齿动物模型中对视网膜神经节细胞体、轴突和树突的神经保护作用，这些模型代表了孤立的高眼压、轴突变性和线粒体变性损伤。我们对视网膜、视神经和上级丘进行了富含小分子量代谢物的代谢组学研究，结果表明，高眼压诱导广泛的代谢紊乱，包括α-酮基谷氨酸、肌酸/肌酐、同型半胱氨酸和甘油磷酸胆碱的一致变化。这种代谢破坏可以通过烟酰胺来防止。烟酰胺通过增加氧化磷酸化、缓冲和预防代谢应激、增加线粒体大小和运动性同时抑制动作电位放电频率来提供进一步的神经保护作用。这些数据支持继续确定长期烟酰胺治疗作为人类青光眼的神经保护治疗的效用。烟酰胺在再现青光眼孤立特征的细胞和动物模型中具有神经保护作用。在基础条件下，全身给予烟酰胺对视觉系统组织的分子副作用有限。烟酰胺在昏迷动物的疾病代谢特征中提供了稳健的逆转。烟酰胺增加氧化磷酸化，缓冲和防止代谢应激，并增加线粒体大小。
Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma. Nicotinamide is neuroprotective in cell and animal models that recapitulate isolated features of glaucoma. Systemic nicotinamide administration has limited molecular side-effects on visual system tissue under basal conditions. Nicotinamide provides a robust reversal in the disease metabolic profile of glaucomatous animals. Nicotinamide increases oxidative phosphorylation, buffers and prevents metabolic stress, and increases mitochondrial size.
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DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
5.3
作者：
Babetto, Elisabetta;Beirowski, Bogdan;Coleman, Michael P.
通讯作者：
Coleman, Michael P.
影响因子：
15.9
作者：
Howell, Gareth R.;Soto, Ileana;John, Simon W. M.
通讯作者：
John, Simon W. M.