Learning Curve for Flow Diversion of Posterior Circulation Aneurysms: A Long-Term International Multicenter Cohort Study.

BACKGROUND AND PURPOSE: Flow diversion has gradually become a standard treatment for intracranial aneurysms of the anterior circulation. Recently, the off-label use of the flow diverters to treat posterior circulation aneurysms has also increased despite initial concerns of rupture and the suboptimal results. This study aimed to explore the change in complication rates and treatment outcomes across time for posterior circulation aneurysms treated using flow diversion and to further evaluate the mechanisms and variables that could potentially explain the change and outcomes. MATERIALS AND METHODS: A retrospective review using a standardized data set at multiple international academic institutions was performed to identify patients with ruptured and unruptured posterior circulation aneurysms treated with flow diversion during a decade spanning January 2011 to January 2020. This period was then categorized into 4 intervals. RESULTS: A total of 378 procedures were performed during the study period. Across time, there was an increasing tendency to treat more vertebral artery and fewer large vertebrobasilar aneurysms (P = .05). Moreover, interventionalists have been increasingly using fewer overlapping flow diverters per aneurysm (P = .07). There was a trend toward a decrease in the rate of thromboembolic complications from 15.8% in 2011-13 to 8.9% in 2018-19 (P = .34). CONCLUSIONS: This multicenter experience revealed a trend toward treating fewer basilar aneurysms, smaller aneurysms, and increased usage of a single flow diverter, leading to a decrease in the rate of thromboembolic and hemorrhagic complications.

Implications of the Collar Sign in Incompletely Occluded Aneurysms after Pipeline Embolization Device Implantation: A Follow-Up Study.

BACKGROUND AND PURPOSE: The angiographic collar sign has been recently described in patients with incompletely occluded aneurysms after Pipeline Embolization Device implantation. The long-term implications of this sign are unknown. We report angiographic outcomes of patients with the collar sign with follow-up of up to 45 months and the implications of this angiographic finding. MATERIALS AND METHODS: We performed a retrospective review of a prospectively maintained data base of patients who underwent Pipeline Embolization Device implantation for an intracranial aneurysm at our institution between January 2014 and December 2016. We included patients with a collar sign at the initial follow-up angiogram after Pipeline Embolization Device implantation. RESULTS: A total of 198 patients with 285 aneurysms were screened for the collar sign on initial and subsequent follow-up angiograms. There were 226 aneurysms (79.3%) with complete occlusion at the first follow-up. Of 59 incompletely occluded aneurysms, 19 (32.2%) aneurysms in 17 patients were found to have a collar sign on the first angiographic follow-up (median, 6 months; range, 4.2-7.2). Ten (52.6%) aneurysms underwent retreatment with a second Pipeline Embolization Device, which resulted in aneurysm occlusion in 1 (10%) patient. There were only 3 (15.8%) aneurysms with complete occlusion at the last follow-up, 2 (10.5%) of which had a single Pipeline Embolization Device implantation and another single (5.3%) aneurysm with a second Pipeline Embolization Device implantation. CONCLUSIONS: A collar sign on the initial angiogram after Pipeline Embolization Device placement is a predictor of poor aneurysm occlusion. Because the occlusion rates remain equally low regardless of retreatment in patients with a collar sign, radiologic follow-up may be more appropriate than retreatment.

Multicenter Postmarket Analysis of the Neuroform Atlas Stent for Stent-Assisted Coil Embolization of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The Neuroform Atlas is a new microstent to assist coil embolization of intracranial aneurysms that recently gained FDA approval. We present a postmarket multicenter analysis of the Neuroform Atlas stent. MATERIALS AND METHODS: On the basis of retrospective chart review from 11 academic centers, we analyzed patients treated with the Neuroform Atlas after FDA exemption from January 2018 to June 2019. Clinical and radiologic parameters included patient demographics, aneurysm characteristics, stent parameters, complications, and outcomes at discharge and last follow-up. RESULTS: Overall, 128 aneurysms in 128 patients (median age, 62 years) were treated with 138 stents. Risk factors included smoking (59.4%), multiple aneurysms (27.3%), and family history of aneurysms (16.4%). Most patients were treated electively (93.7%), and 8 (6.3%) underwent treatment within 2 weeks of subarachnoid hemorrhage. Previous aneurysm treatment failure was present in 21% of cases. Wide-neck aneurysms (80.5%), small aneurysm size (<7 mm, 76.6%), and bifurcation aneurysm location (basilar apex, 28.9%; anterior communicating artery, 27.3%; and middle cerebral artery bifurcation, 12.5%) were common. A single stent was used in 92.2% of cases, and a single catheter for both stent placement and coiling was used in 59.4% of cases. Technical complications during stent deployment occurred in 4.7% of cases; symptomatic thromboembolic stroke, in 2.3%; and symptomatic hemorrhage, in 0.8%. Favorable Raymond grades (Raymond-Roy occlusion classification) I and II were achieved in 82.9% at discharge and 89.5% at last follow-up. mRS ≤2 was determined in 96.9% of patients at last follow-up. The immediate Raymond-Roy occlusion classification grade correlated with aneurysm location (P < .0001) and rupture status during treatment (P = .03). CONCLUSIONS: This multicenter analysis provides a real-world safety and efficacy profile for the treatment of intracranial aneurysms with the Neuroform Atlas stent.

Endothelialization following Flow Diversion for Intracranial Aneurysms: A Systematic Review.

BACKGROUND: The underlying mechanism of action of flow diverters is believed to be the induction of aneurysm thrombosis and simultaneous endothelial cell growth along the device struts, thereby facilitating aneurysm exclusion from the circulation. Although extensive attention has been paid to the role of altered cerebrovascular hemodynamics using computational fluid dynamics analyses, relatively less emphasis has been placed on the role of the vascular endothelium in promoting aneurysm healing. PURPOSE: Our aim was to systematically review all available literature investigating the mechanism of action of flow diverters in both human patients and preclinical models. DATA SOURCES: A systematic search of PubMed, Cochrane Central Register of Controlled Trials MEDLINE, EMBASE, and the Web of Science electronic data bases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. STUDY SELECTION: We selected articles assessing the role of endothelialization in flow-diverter treatment of cerebral aneurysms, including both preclinical and clinical studies. DATA ANALYSIS: Ten articles were eligible for inclusion in this review. Two assessed endothelialization in human patients, while the other 8 used preclinical models (either rabbits or pigs). DATA SYNTHESIS: Methods used to assess endothelialization included optical coherence tomography and scanning electron microscopy. LIMITATIONS: A limitation was the heterogeneity of studies. CONCLUSIONS: Current data regarding the temporal relationship to flow-diverter placement has largely been derived from work in preclinical animal models. Whether these cells along the device struts originate from adjacent endothelial cells or are the result of homing of circulating endothelial progenitor cells is equivocal.

Risk of Branch Occlusion and Ischemic Complications with the Pipeline Embolization Device in the Treatment of Posterior Circulation Aneurysms.

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device is increasingly used for endovascular treatment of intracranial aneurysms due to high reported obliteration rates and low associated morbidity. While obliteration of covered branches in the anterior circulation is generally asymptomatic, this has not been studied within the posterior circulation. The aim of this study was to evaluate the association between branch coverage and occlusion, as well as associated ischemic events in a cohort of patients with posterior circulation aneurysms treated with the Pipeline Embolization Device. MATERIALS AND METHODS: A retrospective review of prospectively maintained databases at 8 academic institutions from 2009 to 2016 was performed to identify patients with posterior circulation aneurysms treated with the Pipeline Embolization Device. Branch coverage following placement was evaluated, including the posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery, and posterior cerebral artery. If the Pipeline Embolization Device crossed the ostia of the contralateral vertebral artery, its long-term patency was assessed as well. RESULTS: A cohort of 129 consecutive patients underwent treatment of 131 posterior circulation aneurysms with the Pipeline Embolization Device. Adjunctive coiling was used in 40 (31.0%) procedures. One or more branches were covered in 103 (79.8%) procedures. At a median follow-up of 11 months, 11% were occluded, most frequently the vertebral artery (34.8%). Branch obliteration was most common among asymptomatic aneurysms (P < .001). Ischemic complications occurred in 29 (22.5%) procedures. On multivariable analysis, there was no significant difference in ischemic complications in cases in which a branch was covered (P = .24) or occluded (P = .16). CONCLUSIONS: There was a low occlusion incidence in end arteries following branch coverage at last follow-up. The incidence was higher in the posterior cerebral artery and vertebral artery where collateral supply is high. Branch occlusion was not associated with a significant increase in ischemic complications.

Collar Sign in Incompletely Occluded Aneurysms after Pipeline Embolization: Evaluation with Angiography and Optical Coherence Tomography.

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device has emerged as an attractive treatment for cerebral aneurysms. Processes involved in aneurysm occlusion include changes in intra-aneurysmal hemodynamics and endothelialization of the device. Here, we call attention to a radiographic sign not previously reported that is detected in incompletely occluded aneurysms after treatment with the Pipeline Embolization Device at angiographic follow-up and referred to as the "collar sign." MATERIALS AND METHODS: A retrospective review of all patients who underwent placement of a Pipeline Embolization Device for cerebral aneurysms between January 2014 and May 2016 was performed. All aneurysms found to show the collar sign at follow-up were included. Optical coherence tomography was performed in 1 case. RESULTS: One hundred thirty-five aneurysms were treated in 115 patients. At angiographic follow-up, 17 (10.7%) aneurysms were found to be incompletely occluded. Ten (58.8%) of these aneurysms (average diameter, 7.9 ± 5.0 mm) were found to have the collar sign at angiographic follow-up (average, 5.5 ± 1.0 months). Four (40.0%) of the aneurysms underwent a second angiographic follow-up (average, 11.0 ± 0.9 months) after treatment, and again were incompletely occluded and showing the collar sign. Two patients underwent retreatment with a second Pipeline Embolization Device. Optical coherence tomography showed great variability of endothelialization at the proximal end of the Pipeline Embolization Device. CONCLUSIONS: The collar sign appears to be indicative of endothelialization, but continued blood flow into the aneurysm. This is unusual given the processes involved in aneurysm occlusion after placement of the Pipeline Embolization Device and has not been previously reported.

Treatment of Tandem Internal Carotid Artery Aneurysms Using a Single Pipeline Embolization Device: Evaluation of Safety and Efficacy.

BACKGROUND AND PURPOSE: Tandem aneurysms are defined as multiple aneurysms located in close proximity on the same parent vessel. Endovascular treatment of these aneurysms has rarely been reported. Our aim was to evaluate the safety and efficacy of a single Pipeline Embolization Device for the treatment of tandem aneurysms of the internal carotid artery. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the Pipeline Embolization Device between 2009 and 2016 at 3 institutions in the United States was performed. Cases included aneurysms of the ICA treated with a single Pipeline Embolization Device, and they were divided into tandem versus solitary. Angiographic and clinical outcomes were compared. RESULTS: The solitary group (median age, 58 years) underwent 184 Pipeline Embolization Device procedures for 184 aneurysms. The tandem group (median age, 50.5 years) underwent 34 procedures for 78 aneurysms. Aneurysms were primarily located along the paraophthalmic segment of the ICA in both the single and tandem groups (72.3% versus 78.2%, respectively, P = .53). The median maximal diameters in the solitary and tandem groups were 6.2 and 6.7 mm, respectively. Complete occlusion on the last angiographic follow-up was achieved in 75.1% of aneurysms in the single compared with 88.6%% in the tandem group (P = .06). Symptomatic thromboembolic complications were encountered in 2.7% and 8.8% of procedures in the single and tandem groups, respectively (P = .08). CONCLUSIONS: Tandem aneurysms of the ICA can be treated with a single Pipeline Embolization Device with high rates of complete occlusion. While there appeared to be a trend toward higher thromboembolic complication rates, this did not reach statistical significance.

Predictors of Incomplete Occlusion following Pipeline Embolization of Intracranial Aneurysms: Is It Less Effective in Older Patients?

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device (PED) for the treatment of intracranial aneurysms is associated with a high rate of aneurysm occlusion. However, clinical and radiographic predictors of incomplete aneurysm occlusion are poorly defined. In this study, predictors of incomplete occlusion at last angiographic follow-up after PED treatment were assessed. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the PED between 2009 and 2016, at 3 academic institutions in the United States, was performed. Cases with angiographic follow-up were selected to evaluate factors predictive of incomplete aneurysm occlusion at last follow-up. RESULTS: We identified 465 aneurysms treated with the PED; 380 (81.7%) aneurysms (329 procedures; median age, 58 years; female/male ratio, 4.8:1) had angiographic follow-up, and were included. Complete occlusion (100%) was achieved in 78.2% of aneurysms. Near-complete (90%-99%) and partial (<90%) occlusion were collectively achieved in 21.8% of aneurysms and defined as incomplete occlusion. Of aneurysms followed for at least 12 months (211 of 380), complete occlusion was achieved in 83.9%. Older age (older than 70 years), nonsmoking status, aneurysm location within the posterior communicating artery or posterior circulation, greater aneurysm maximal diameter (≥21 mm), and shorter follow-up time (<12 months) were significantly associated with incomplete aneurysm occlusion at last angiographic follow-up on univariable analysis. However, on multivariable logistic regression, only age, smoking status, and duration of follow-up were independently associated with occlusion status. CONCLUSIONS: Complete occlusion following PED treatment of intracranial aneurysms can be influenced by several factors related to the patient, aneurysm, and treatment. Of these factors, older age (older than 70 years) and nonsmoking status were independent predictors of incomplete occlusion. While the physiologic explanation for these findings remains unknown, identification of factors predictive of incomplete aneurysm occlusion following PED placement can assist in patient selection and counseling and might provide insight into the biologic factors affecting endothelialization.

Increased levels of plasma cholesteryl ester hydroperoxides in patients with subarachnoid hemorrhage.

The pathophysiology of subarachnoid hemorrhage (SAH) may involve free radical production and lipid peroxidation. We examined plasma levels of cholesteryl ester hydroperoxides (CEOOH) and antioxidants in 25 patients with SAH, and 10 neurologic controls with lacunar stroke. Patients with SAH had significantly increased plasma levels of CEOOH, which peaked on day 5 after the ictus. Concentrations of CEOOH were significantly increased, and ascorbic acid concentrations were significantly decreased in patients who developed vasospasm compared with patients without vasospasm. Increased levels of CEOOH were associated with increased mortality and correlated with clinical outcome scales. These results implicate oxidative stress in the pathogenesis of SAH and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.

Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome.

OBJECTIVE: To investigate the causes of fever in subarachnoid hemorrhage (SAH) and examine its relationship to outcome. BACKGROUND: Fever adversely affects outcome in stroke. Patients with SAH are at risk for cerebral ischemia due to vasospasm (VSP). In these patients, fever may be both caused by, and potentiate, VSP-mediated brain injury. METHODS: The authors prospectively studied patients admitted to a neurologic intensive care unit with nontraumatic SAH, documenting Hunt-Hess grade, Fisher group, Glasgow Coma Score, bacterial culture data, daily transcranial Doppler mean velocities, and maximum daily temperatures. Patients were classified as febrile (temperature above 38.3 degrees C for at least 2 consecutive days) or afebrile (no fever or isolated episodes of temperature above 38.3 degrees C). VSP was verified by either transcranial Doppler or angiographic criteria. Rankin scale scores on discharge were dichotomized into good (0 to 2) or poor (3 to 6) outcomes. RESULTS: Ninety-two consecutive patients were studied. Thirty-eight patients were classified as febrile. No source for infection was found in 10 of 38 (26%) patients. In a multivariate analysis, three variables independently predicted fever occurrence: ventriculostomy (OR, 8.5 [CI, 2.4 to 29.7]), symptomatic VSP (OR, 5.0 [CI, 1.03 to 24.5]), and older age (OR, 1.75 per 10 years [CI, 1.02 to 3.0]). Poor outcome was related to fever (OR, 1.4 per each day febrile [CI, 1.1 to 1.88]), older age (OR, 1.64 per 10 years [CI, 1.04 to 2.58]), and intubation (OR, 21.8 [CI, 5.6 to 84.5]). CONCLUSION: Fever in SAH is associated with vasospasm and poor outcome independently of hemorrhage severity or presence of infection.

A modified gold chloride technique for optimal impregnation of nerves within corneal whole mounts and dura of the albino rat.

Ranvier's method of staining tissue whole mounts with gold chloride to visualize nerve fibers was modified by lengthening the incubation time in gold chloride and reducing the time in acidulated water. These simple modifications of an old technique give consistent impregnation of nerve fibers with light background staining in whole mounts of cornea and dura.

Changes in corneal innervation during postnatal development in normal rats and in rats treated at birth with capsaicin.

This study was undertaken to learn more about the keratitis that follows the neonatal administration of capsaicin to rats. In the first part of the study the density and pattern of corneal innervation were followed throughout postnatal development in litters of control rats and in rats that received capsaicin as neonates. In rats treated with capsaicin, the density of corneal innervation was lower than that of control rats until 28 days of age. Thereafter nerve fiber sprouting was observed within the corneas of capsaicin-treated rats. By 56 days of age the capsaicin-treated rats had a denser corneal innervation than did control rats. In the second part of the study the incidence and severity of the corneal trophic changes induced by capsaicin were studied in litters of rats treated with chronic tarsorrhaphy and in litters raised in the dark. Neither of these manipulations altered the incidence or severity of keratitis. These observations demonstrate that sprouting of the remaining corneal axons is related temporally to the previously observed decrease in keratitis. Furthermore the more severe keratitis observed in early postnatal life does not appear to be related to physical injury of the cornea.

Sprouting of corneal sensory fibers in rats treated at birth with capsaicin.

Normal structure and function of corneal epithelium is known to be related to proper innervation. To investigate possible trophic actions of sensory neurons on corneal epithelium, corneal innervation and various physical parameters were studied in normal rats and in rats treated as neonates with intraperitoneal injections of capsaicin. Corneal lesions were noted in treated rats which varied from multiple punctate areas of corneal opacity to deep stromal opacity with ulceration and neovascularization. These lesions waxed and waned throughout the animal's life. In addition, mechanical threshold of the corneal reflex was higher in capsaicin-treated rats. The tear rate in response to a provocative test was diminished in treated rats, presumably due to reduced afferent trigeminal input to the brain stem; blinking rates were more frequent in these animals. Using fluorescent retrograde tracing techniques, the number of cells innervating the cornea in capsaicin-treated rats was found to be significantly less compared with control animals. Innervation in the cornea (examined using a gold chloride technique) demonstrated a decrease in the number of corneal large axons in treated rats with neurite sprouting of these axons yielding a higher density of nerve fibers compared with controls. Thus, sprouting of residual sensory neurons occurs in response to the partial corneal denervation produced by capsaicin, and this sprouting does not functionally compensate to prevent the development of chronic keratitis.

Nitric oxide modulates light-evoked compound action potentials in the intact rabbit retina.

This study examines the effects of alterations in nitric oxide (NO) production on rabbit retinal function. NG-nitro-L-arginine (L-NA) and L-arginine (L-Arg) inhibited the light-evoked compound action potentials (CAPs) from the optic nerve, but not the electroretinogram (ERG), in a concentration-dependent manner, whereas D-arginine had no effect. L-Arg partially reversed the L-NA-induced inhibitory effect, and L-NA prevented the L-Arg-induced attenuation of the CAPs. Sodium nitroprusside reduced both the CAPs and the ERG, whilst potassium ferricyanide did not affect the CAPs, and potentiated the ERG. We conclude that, independent of the vasculature, endogenous NO modulates neurotransmission (i.e. light-evoked CAPs), but probably not phototransduction (i.e. light-evoked ERG) in this intact in vitro central nervous system preparation.

Nitric oxide produced during ischemia improves functional recovery in the rabbit retina.

We examined the effect of modulating endogenous nitric oxide (NO) production on the recovery of neuronal function from temporary ischemia using a preparation in which blood flow is not a factor. Inhibition of nitric oxide synthase (NOS) during ischemia with L-NA (100 mumol-1) resulted in worse functional recovery compared to D-NA (100 mumol-1)-treated in control retinas (p < 0.01). In contrast, addition of L-Arg (1000 mumol-1) during ischemia, resulted in a concentration-dependent functional improvement (p < 0.05). These results show that inhibition of constitutive NOS is detrimental, whilst the enhancement of endogenous NO production improves the recovery of neuronal function during a period of temporary ischemia in the isolated retina, (an in vitro avascular model of the CNS). Thus, independent of its effects on the vasculature, NO production during temporary ischemia protects neurons from irreversible function damage.

Magnesium plus mexiletine inhibit energy usage and protect retinas against ischemia.

We determined whether exogenous Mg2+ and/or mexiletine (Mex), which are reported to be neuroprotective agents, reduced neuronal energy requirements and protected against ischemia, using isolated rabbit retinas. Under non-ischemic conditions, Mex (300 microM) and the combination of Mg2+ (1 mM) plus Mex (300 microM) significantly reduced glucose utilization, by 19% and 31%, respectively. The combination of Mg2+ plus Mex, but not either agent alone, significantly reduced lactate production (by 18%; p < 0.05). When added during 2 h of ischemia (simulated by the reduction of oxygen from 95% to 15% and of glucose from 6 mM to 1 mM), Mg2+ plus Mex improved the recovery of glucose utilization (p < 0.01), lactate production (p < 0.05) and neuronal function (p < 0.05) for 3 h following return to control (post-ischemia/recovery) conditions. Thus reducing energy demands by blocking functions during temporary ischemia, protects neurons from irreversible functional damage.

A quantitative analysis of the retrograde axonal transport of 4 different fluorescent dyes in peripheral sensory and motor neurons and lack of anterograde transport in the corticospinal system.

Many fluorescent dye compounds are transported by axons in retrograde and anterograde directions. In the present study the uptake and retrograde axonal transport of 4 chemically related fluorescent dyes was evaluated in the peripheral nervous system of adult mice. Anterograde transport was studied in the corticospinal tract of adult rats. In addition to confirming the previously reported intra-axonal transport of Rhodamine-B-isothiocyanate, we report the transport of Rhodamine-X-isothiocyanate. Sulforhodamine-101-acid chloride and Lissamine rhodamine-B-sulfonyl chloride. By using the fluorescence intensity of the labeled motor and sensory neurons as well as cell counts of fluorescently labeled motor neurons and percent of labeled dorsal root ganglia (DRG) cells, we were able to quantitate the amount of retrograde transport of a given fluorescent compound. The two dyes with isothiocyanate groups available for conjugation were transported in higher amounts compared to the dyes containing sulfonyl chloride groups. No anterograde transport in the corticospinal system was observed. We conclude that the 4 dyes described are useful for retrograde neuroanatomical tracing experiments. We describe methods for quantifying the amount of retrograde transport by peripheral motor and sensory neurons.

Acetylsalicylate administered during simulated ischemia reduces the recovery of neuronal function in the in vitro rabbit retina.

Aspirin is widely used as an analgesic, in the secondary prevention of stroke, and has recently been suggested to be a putative neuroprotective agent, yet whether it acts directly on the central nervous system (CNS) is not yet clarified. We therefore examined the effect of lysine acetylsalicylate (L-ASA, 4-2000 microM) on neuronal function under normal conditions and following 1 h of ischemia using the in vitro rabbit retina preparation. L-ASA inhibited the light-evoked compound action potentials, but not the electroretinogram, in a concentration-dependent manner. In addition, L-ASA (2000 microM, but not 4, 40 or 200 microM) administered during ischemia, reduced the recovery of neuronal function compared to control (untreated) retinas. L-ASA therefore inhibits CNS neurotransmission, but not phototransduction, in a concentration-dependent manner. In addition, high concentration L-ASA impairs the recovery of neuronal function following an ischemic episode.

Post-treatment with nicotinamide (vitamin B(3)) reduces the infarct volume following permanent focal cerebral ischemia in female Sprague-Dawley and Wistar rats.

Delayed treatment with nicotinamide (NAm) protects male rats against cerebral ischemia. Since the preponderant use of male animals in stroke research may produce results not applicable to female stroke patients due to gender-related differences, we examined whether delayed NAm treatment could protect female rats against focal cerebral ischemia using a model of permanent middle cerebral artery occlusion (MCAo). NAm (500 mg/kg) given intravenously, 2 h after MCAo, significantly reduced the infarct volume of female Sprague-Dawley (55%, P<0.05) and Wistar rats (60%, P<0.05) rats when compared with saline-injected controls. These studies confirm that NAm is neuroprotective specifically at the dose of 500 mg/kg in rats. The novel findings are that this neuroprotection occurs in female, as well as male rats, and that the neuroprotection observed is more robust when administered as an intravenous bolus compared with intraperitoneal administration.

Nicotinamide reduces infarction up to two hours after the onset of permanent focal cerebral ischemia in Wistar rats.

Ischemia depletes ATP and initiates cascades leading to irreversible tissue injury. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+) which increases neuronal ATP concentration and protects against malonate-induced neurotoxicity, trauma and nitric oxide toxicity. We therefore examined whether nicotinamide could protect against stroke, using a model of permanent middle cerebral artery occlusion (MCA) occlusion in Wistar rats. Nicotinamide reduced neuronal infarction in a dose-specific manner. Furthermore, nicotinamide (500 mg/kg) reduced infarcts when administered up to 2 h after the onset of permanent MCA occlusion. The mechanism of action underlying the neuroprotection observed with nicotinamide remains to be clarified. These results are potentially important since nicotinamide is already used clinically, though not in the treatment of stroke.