Delayed Treatment with Carboxy-PTIO Permits a 4-h Therapeutic Window of Opportunity and Prevents Against Ischemia-Induced Energy Depletion Following Permanent Focal Cerebral Ischemia in Mice

Abstract

We examined whether a nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-L: -oxyl-3-oxide (carboxy-PTIO), could offer neuroprotective actions and improve cerebral energy metabolism in a model of stroke. Sixty C57BL/10J mice were given either carboxy-PTIO (0.3-1.2 mg/kg) or vehicle intraperitoneally, 0.5 h after permanent middle cerebral artery occlusion, to evaluate the dose-response effects. An additional 70 animals received carboxy-PTIO (0.6 mg/kg) or vehicle, 2-6 h post-ischemia, for establishing the therapeutic window. Subgroups of animals, treated with carboxy-PTIO (0.6 mg/kg) or vehicle, were used for measuring cerebral bioenergetic metabolites (ATP, ADP, AMP, adenosine). Mice treated with carboxy-PTIO (0.6 mg/kg) had dose-specifically reduced brain infarction, significantly by 27-30% (P < 0.05), even when therapy was delayed up to 4 h after the ischemic insult (P < 0.05). Four hour post-ischemia, ATP depleted in the ischemic hemisphere (P < 0.05). Administration with carboxy-PTIO not only improved the recovery of ATP in the ischemic hemisphere (P < 0.05), but also enhanced adenosine content across the ischemic and non-ischemic hemispheres (P < 0.05). The neuroprotection of carboxy-PTIO may be partly attributed to the beneficial effects of improving cerebral energy metabolism.

Magnolol Reduces Glutamate-Induced Neuronal Excitotoxicity and Protects against Permanent Focal Cerebral Ischemia Up to 4 Hours

“…Exactly by which mechanisms in the glutamate-stimulated cultured neurons the dose-responsive regimen seen with magnolol for cell swelling inhibition was inconsistent with the “U-shaped” hormetic response observed for inhibiting the rises of [Ca 2+ ](i) remains to be elucidated [18], [19]. Curiously, hormetic neuroprotective responses were also observed in the magnolol-treated stroke animals in which a low-dosing regimen was ineffective whereas high dosage (200 mg/kg) induced adverse effects along with a temperature-lowering action [12], [20], [21].…”

“…Perhaps using multiple effective, smaller doses of magnolol, combined with an intravenous administration route, the therapeutic window may be extended and/or the degree of neuroprotection improved [8], [19]. Further studies are needed to determine whether magnolol can protect against reperfusion damage and late-onset ischemic insults following cerebral ischemia/reperfusion after a prolonged reperfusion period [23].…”

“…Successful MCA occlusion was ensured by a sharp decrease of local cortical blood perfusion (LCBP) to about 20% of baseline as determined by Laser-Doppler flowmetry (LDF, Laserflo BMP 2 , Vasamedics, St. Paul, MN) [8], [9], [19], [23], [31].…”

“…The brain was cut into 2 mm coronal sections using a rat brain matrix (RBM 4000 C, ASI Instrument, Inc., Warren, MI) and stained according to standard 2, 3, 5-triphenyltetrazolium chloride (TTC) method [8], [24]. Briefly, the brain was cut into 2 mm coronal sections using a rat brain matrix (RBM 4000 C, ASI Instrument, Inc., Warren, MI) and stained according to the standard 2, 3, 5-triphenyltetrazolium chloride (TTC) method [8], [19], [24]. A total of 7 brain sections were traced and measured using a computerized image analyzer (MCID Elite).…”

Melatonin improves presynaptic protein, SNAP‐25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats

“…Under light microscopy, the areas of neuronal perikarya displaying typical morphological features of ischemic damage were delineated [5, 23, 45]. Brain infarction were measured using a computerized image analyzer (MCID Elite, Imaging Research Inc., Ontario, Canada), as described previously [5, 23, 45–47], and were expressed as a percentage of the contralateral hemisphere volume [48]. In addition, individual cortical and subcortical (caudoputaminal and hippocampal) infarct sizes were separately calculated.…”