High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats

Antezana, David; Clatterbuck, Richard E.; Alkayed, Nabil J.; Murphy, Stephanie J.; Anderson, Lauren G.; Frazier, James L.; Hurn, Patricia D.; Traystman, Richard J.; Tamargo, Rafael J.

doi:10.3171/jns.2003.98.4.0860

Cited by 43 publications

(23 citation statements)

References 49 publications

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“…The maximal adult human U.S. Food and Drug Administration approved dosage is 3200 mg=d without an adjustment for weight, equivalent to 46-64 mg=kg=d in a 50-70 kg person. The maximal tolerated dose in rats is between 240 and 375 mg=kg=d (Antezana et al, 2003;Melarange et al, 1992;Wax et al, 1975), and other neurological conditions have been treated with 56-120 mg=kg=d in rodents (Antezana et al, 2003;Fu et al, 2007;Lim et al, 2000;Lopez et al, 2006;Park et al, 2005;Richardson et al, 2005). In the studies detailed here, treatment continued for 4 weeks at a dosage of 70 mg= kg=d of ibuprofen.…”

Section: Improved Recovery From Spinal Contusion After Subacute Theramentioning

confidence: 99%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

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The GTP-binding protein RhoA regulates microfilament dynamics in many cell types and mediates the inhibition of axonal regeneration by myelin and chondroitin sulfate proteoglycans. Unlike most other nonsteroidal anti-inflammatory drugs, ibuprofen suppresses basal RhoA activity (Zhou et al., 2003). A recent report suggested that ibuprofen promotes corticospinal axon regeneration after spinal cord injury (Fu et al., 2007). Here, we confirm that ibuprofen reduces ligand-induced Rho signaling and myelin-induced inhibition of neurite outgrowth in vitro. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord contusion, animals recovered walking function to a greater degree, with twice as many rats achieving a hind limb weight-bearing status. We examined the relative role of tissue sparing, axonal sprouting, and axonal regeneration in the action of ibuprofen. Histologically, ibuprofen-treated animals display an increase in spared tissue without an alteration in astrocytic or microglial reaction. Ibuprofen increases axonal sprouting from serotonergic raphespinal axons, and from rostral corticospinal fibers in the injured spinal cord, but does not permit caudal corticospinal regeneration after spinal contusion. Treatment of mice with complete spinal cord transection demonstrates long-distance raphespinal axon regeneration in the presence of ibuprofen. Thus, administration of ibuprofen improves the recovery of rats from a clinically relevant spinal cord trauma by protecting tissue, stimulating axonal sprouting, and allowing a minor degree of raphespinal regeneration.

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Section: Improved Recovery From Spinal Contusion After Subacute Theramentioning

confidence: 99%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

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“…With respect to ischemia, particular attention has been given to the possible role of arachidonic acid metabolites in the regulation of postinjury cerebral blood flow (Furlow and Hallenbeck, 1978;Black et al, 1984;Kochanek et al, 1988;Wahl et al, 1993;Zuckerman et al, 1994) and the formation of vasogenic brain edema (Bhakoo et al, 1984;Hall and Travis, 1988;Katayama et al, 1990). However, preischemic administration of nonselective cyclooxygenase inhibitors can also have a positive effect on histological neuronal outcome after ischemic insults (Sasaki et al, 1988;Nakagomi et al, 1989;Costello et al, 1990;Cole et al, 1993;Patel et al, 1993;Antezana et al, 2003). Whether the neuronal protective effect of nonsteroidal antiinflammatory drugs (NSAIDs) observed in the above-mentioned studies was due to a direct cytoprotection or to favorable hemodynamics could not be ascertained.…”

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confidence: 95%

Naproxen Reduces Excitotoxic Neurodegeneration in Vivo with an Extended Therapeutic Window

Silakova¹,

Hewett²,

Hewett³

2004

J Pharmacol Exp Ther

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The purpose of this study was to examine the optimal dose and therapeutic window of opportunity of the nonsteroidal antiinflammatory drug naproxen in an animal model of excitotoxic neuronal injury. Injection of N-methyl-D-aspartate (NMDA; 18 -20 nmol) into the CA1 region of the left hippocampus resulted in significant brain edema as measured by the percentage of total forebrain water content that occurred 24 h after intrahippocampal microinjection of NMDA with Ϸ50% loss of CA1 neurons assessed 72 h later. Naproxen pretreatment (20 mg/kg) resulted in significantly less brain edema. Ten, 15, or 20 mg/kg naproxen, administered systemically 1 day (b.i.d.) before and for 3 days after (b.i.d.) NMDA injection, attenuated the neuronal damage by 27.2 Ϯ 7.8, 39.6 Ϯ 11.1, and 57.0 Ϯ 5.2%, respectively. By comparison, a single dose of MK-801 (2 mg/kg i.p.) given 20 min before NMDA injection inhibited subsequent hippocampal injury by 65.6 Ϯ 8.8%. Most importantly, neuroprotection was still evident when naproxen treatment (20 mg/kg i.p.) was initiated 6 h after NMDA microinjection. Protection was lost if administration of naproxen was delayed for 20 h. These findings demonstrate that naproxen can prevent excitotoxic neuronal injury in vivo, that it is nearly as effective as direct NMDA receptor antagonism, and that it has an extended therapeutic time window. As such, naproxen may be a particularly promising pharmaceutical for the treatment of neurological diseases associated with overactivation of NMDA receptors.

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“…12,13 Intravenous injection of 10 mg kg À1 in children is associated with good penetration of cerebrospinal fluid, with a peak concentration attained after 30-40 min. 18 The use of the oral form of ibuprofen was advocated in our study because of its affordable pricing that would make it widely available, especially in the regions with the highest incidence of HIE.…”

Section: Discussionmentioning

confidence: 99%

“…10 Ibuprofen can inhibit the production of proinflammatory cytokines and oxyradicals, 11 and poses a long-lasting protective effect to the brain against global and focal ischemia in animals. 12,13 In spite of the experimental evidence for a potentially neuroprotective role of ascorbic acid and ibuprofen, the efficacy of these two drugs has not been studied in infants with HIE. As the cascade of events following HI injury is a complex one, it is unlikely that a single agent will be successful in ameliorating the effect of HI injury.…”

Section: Introductionmentioning

confidence: 99%

Ascorbic acid combined with ibuprofen in hypoxic ischemic encephalopathy: a randomized controlled trial

et al. 2009

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Objective: Free oxygen radicals and proinflammatory cytokines are important causes for brain injury in neonates with hypoxic ischemic encephalopathy (HIE). Our objectives were to test the hypothesis that a combination of antioxidants (ascorbic acid) and anti-inflammatory agents (ibuprofen) can ameliorate the brain injury in HIE and improve neurodevelopmental outcomes when given to term infants immediately after birth.Study Design: In a prospective, randomized, double-blinded controlled trial, 60 asphyxiated term infants were assigned to one of two groups, intervention and control. The intervention group (n ¼ 30) received intravenous ascorbic acid and oral ibuprofen for 3 days; and the control group (n ¼ 30) received similar volumes of a placebo. We measured a panel of cytokines at enrollment and administered the treatment drugs within 2 h after birth. Neurological evaluations and developmental screenings were performed for all survivors at 6 months of age.Result: The Intervention and Control groups did not differ in the severity of HIE at enrollment, the concentrations of IL-1b and IL-6, the incidence of mortality (37 vs 33%), the incidence of neurological abnormalities at hospital discharge (47 vs 55%) and the incidence of developmental delay at 6 months of age (32 vs 40%), respectively. None of the observed complications were related to intervention. Serum interleukin (IL)-1b and IL-6 concentrations correlated positively with the severity of HIE at birth (P<0.01), whereas only serum IL-6 correlated with neurodevelopmental outcome at 6 months (P<0.001).Conclusion: Early administration of ascorbic acid and ibuprofen did not affect outcomes in infants with perinatal asphyxia. This study does not explain whether our intervention was not effective in blocking free radicals and inflammatory cytokines, if the dosing and route of administration were inadequate, or if other mediators existed that could have a more powerful role in brain injury during hypoxia-ischemia.

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High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats

Cited by 43 publications

References 49 publications

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Naproxen Reduces Excitotoxic Neurodegeneration in Vivo with an Extended Therapeutic Window

Ascorbic acid combined with ibuprofen in hypoxic ischemic encephalopathy: a randomized controlled trial

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