Delayed Multidose Treatment with Nicotinamide Extends the Degree and Duration of Neuroprotection by Reducing Infarction and Improving Behavioral Scores up to Two Weeks Following Transient Focal Cerebral Ischemia in Wistar Rats

Maynard, Kenneth I.; Ayoub, Issam A.; Shen, Chiung‐Chyi

doi:10.1111/j.1749-6632.2001.tb03653.x

Cited by 26 publications

(16 citation statements)

References 28 publications

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“…Measurement of injury by loss of brain weight or volume, by gross pathological examination score and by neurofunctional assessment of motor coordination on the rotorod, all show a neuroprotective effect of nicotinamide. Similar results have been described in adult animals [3,4,17,27,28,33,34,41]. Delayed neuronal injury sometimes requires a prolonged period to develop [39].…”

Section: Discussionsupporting

confidence: 75%

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Feng¹,

Paul²,

LeBlanc³

2006

Brain Research Bulletin

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Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 ± 3.6% in vehicle pups (n = 28) to 11.9 ± 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F 2α measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 ± 7 pg/g in the shams (n = 6), 175 ± 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 ± 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

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Section: Discussionsupporting

confidence: 75%

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Feng¹,

Paul²,

LeBlanc³

2006

Brain Research Bulletin

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“…We believe that this occurred partially because of the use of the more robust model of intraluminal suture pMCAO, which caused larger insults than models of transient MCAO. Note that in all previous reports using NAm in the treatment of transient focal cerebral ischemia in four independent laboratories, including ours, positive behavioral outcomes were consistently reported (Mokudai et al, 2000;Maynard et al, 2001a;Yang et al, 200 2b;Gupta et al, 2004). Our finding underscores the important point that insults from permanent (suture) models of MCAO are larger and more difficult to treat than lesions from transient (suture) MCAO (Ren and Finklestein, 2005).…”

Section: Discussionsupporting

confidence: 82%

“…Secondly, we tested NAm in a model of permanent, rather than transient, MCAO. Thirdly, NAm treatment was administered intravenously for improved brain protection Maynard et al, 2001a) at 2 h after the onset of pMCAO versus 90 min MCAO followed by reperfusion. Permanent vascular occlusion is a powerful stimulus for inducing degradation of intracellular ATP in the territory of the supplying cerebral vasculature.…”

Section: Mcao-saline (N=10)mentioning

confidence: 99%

Delayed Treatment with Nicotinamide Inhibits Brain Energy Depletion,Improves Cerebral Microperfusion, Reduces Brain Infarct Volume, but does not Alter Neurobehavioral Outcome Following Permanent Focal Cerebral Ischemia in Sprague Dawley Rats

Lee

Wu²,

Chang

et al. 2006

CNR

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Delayed treatment with nicotinamide (NAm) reduces infarction induced by middle cerebral artery occlusion (MCAO) in rats. This study explored some potential mechanisms by which delayed NAm treatment may confer protection in the brain of Sprague-Dawley rats following permanent MCAO (pMCAO). NAm (500 mg/kg) or vehicle was given 2 h after the onset of pMCAO. Cortical microperfusion, brain and rectal temperature were serially measured. Neurobehavioral examinations were performed at 24 h post-ischemia followed by sacrifice for histologic assessment. Some rats were also sacrificed at 4 h post-ischemia for analyses of ATP, ADP, AMP, and adenosine. Permanent MCAO induced spontaneous hyperthermia and a sharp decrease in cortical microperfusion, ATP concentration, and the sum of adenine nucleotides (p < 0.05). At 4 h post-ischemia, NAm improved ATP recovery, the sum of adenine nucleotides (p < 0.05) and attenuated the ischemia-induced systemic hyperthermia (p < 0.05) without affecting brain temperature or cortical microperfusion. At 24 h, NAm improved cortical microperfusion in the ischemic hemisphere and reduced total infarct volume (p < 0.05), but did not affect behavioral scores. The data suggest that NAm attenuated brain damage following pMCAo initially by improving cerebral bioenergetic metabolism during the sub-acute phase of ischemia, followed by a delayed improvement in microvascular perfusion.

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“…There were 10 full articles [11][12][13][14][15][16][17][18][19][20] and 8 abstracts. [21][22][23][24][25][26][27][28] Four abstracts described work that was also described in full articles, 21,22,26,28 and 1 further abstract has been published in full since the search was performed.…”

Section: Resultsmentioning

confidence: 99%

Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias

Macleod

O’Collins

Howells

et al. 2004

Stroke

563

468

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Background and Purpose-The extensive neuroprotective literature describing the efficacy of candidate drugs in focal ischemia has yet to lead to the development of effective stroke treatments. Ideally, the choice of drugs taken forward to clinical trial should be based on an unbiased assessment of all available data. Such an assessment might include not only the efficacy of a drug but also the in vivo characteristics and limits-in terms of time window, dose, species, and model of ischemia used-to that efficacy. To our knowledge, such assessments have not been made. Nicotinamide is a candidate neuroprotective drug with efficacy in experimental stroke, but the limits to and characteristics of that efficacy have not been fully described. Methods-Systematic review and modified meta-analysis of studies of experimental stroke describing the efficacy of nicotinamide. The search strategy ensured ascertainment of studies published in full and those published in abstract only. DerSimonian and Laird random effects meta-analysis was used to account for heterogeneity between studies. Results-Nicotinamide improved outcome by 0.287 (95% confidence interval 0.227 to 0.347); it was more effective in temporary ischemia models, after intravenous administration, in animals without comorbidities, and in studies published in full rather than in abstract. Studies scoring highly on a quality measure gave more precise estimates of the global effect. Conclusions-Meta-analysis provides an effective technique for the aggregation of data from experimental stroke studies.We propose new standards for reporting such studies and a systematic approach to aggregating data from the neuroprotective literature.

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Delayed Multidose Treatment with Nicotinamide Extends the Degree and Duration of Neuroprotection by Reducing Infarction and Improving Behavioral Scores up to Two Weeks Following Transient Focal Cerebral Ischemia in Wistar Rats

Cited by 26 publications

References 28 publications

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Delayed Treatment with Nicotinamide Inhibits Brain Energy Depletion,Improves Cerebral Microperfusion, Reduces Brain Infarct Volume, but does not Alter Neurobehavioral Outcome Following Permanent Focal Cerebral Ischemia in Sprague Dawley Rats

Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias

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