General Anesthetic Use in Fragile X Spectrum Disorders.

The fragile X premutation is characterized by a repeat expansion mutation (between 55 to 200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene, which leads to RNA toxicity at the cellular level. This may cause patients with the premutation to be particularly susceptible to environmental toxins, which could manifest clinically as new or worsening ataxia and memory loss. Multiple published case reports have also suggested general anesthetics as a potential toxin leading to negative side effects when used in patients with fragile X-associated disorders. However, at this time, there have been no formal research studies regarding cellular changes or long-term clinical manifestations after general anesthetic use in this population. This review aims to highlight previous case reports regarding sequelae related to general anesthetic use in fragile X-associated disorders. New case reports related to this phenomenon are also included.

Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia.

BACKGROUND: This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia-reperfusion using dexmedetomidine, an α2-adrenoreceptor agonist and a sedative. METHODS: Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 µg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 µm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. RESULTS: Ischemia-reperfusion decreased microregional SvO2 (52.9 ± 3.7% vs. 61.1 ± .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 × standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 ± 2.2% vs. 12.6 ± 1.5%, P < .005). CONCLUSIONS: In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction.

Effects of the thioredoxin-1 inhibitor PX-12 on blood-brain barrier permeability in the early stage of focal cerebral ischemia.

BACKGROUND/AIMS: Since a thioredoxin-1 (Trx-1) inhibitor, 1-methylpropyl-2-imidazolyl disulfide (PX-12) which is an antitumor agent, significantly decreased vascular permeability in tumor xenografts within a few hours of treatment, we tested whether PX-12 would attenuate blood-brain barrier (BBB) disruption in the early stage of focal cerebral ischemia and whether its action could be affected by vascular endothelial growth factor (VEGF) which interacts with the Trx-1 system. METHODS: In rats, 40 min after intravenous infusion of either 25 mg/kg of PX-12 (PX-12 group) or normal saline (control group), a middle cerebral artery (MCA) was occluded. In half of each group, VEGF (10(-10) mol/l) was applied topically in the ischemic cortex (IC). Ninety minutes after MCA occlusion, the transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid and the volume of (3)H-dextran distribution were determined to measure the degree of BBB disruption. VEGF protein levels were determined using Western blot analysis. RESULTS: MCA occlusion increased the Ki in the control (+196%) as well as in the PX-12-treated rats (+90%), but the Ki of the IC of the PX-12 group was lower (-42%) than that of the control rats. VEGF protein levels were decreased in both the IC (-9.5%) and the contralateral cortex (CC; -10.2%) with PX-12 treatment. In the VEGF-treated rats, PX-12 also attenuated (-41%) the Ki of the IC. The difference in the volume of dextran distribution between the IC and the CC became insignificant with PX-12 treatment with or without VEGF application. CONCLUSION: Our data demonstrated that PX-12 was effective in decreasing BBB disruption in the early stage of focal cerebral ischemia and that VEGF is not an important factor involved in the action of PX-12 on BBB permeability.

Cerebral ischemia and reperfusion increases the heterogeneity of local oxygen supply/consumption balance.

BACKGROUND AND PURPOSE: After cerebral vessel blockage, local blood flow and O2 consumption becomes lower and oxygen extraction increases. With reperfusion, blood flow is partially restored. We examined the effects of ischemia-reperfusion on the heterogeneity of local venous oxygen saturation in rats in order to determine the pattern of microregional O2 supply/consumption balance in reperfusion. METHODS: The middle cerebral artery was blocked for 1 hour using the internal carotid approach in 1 group (n=9) and was then reperfused for 2 hours in another group (n=9) of isoflurane-anesthetized rats. Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: After 1 hour of ischemia, local cerebral blood flow (92±10 versus 50±10 mL/min per 100 g) and O2 consumption (4.5±0.6 versus 2.7±0.5 mL O2/min per 100 g) decreased compared with the contralateral cortex. Oxygen extraction increased (4.7±0.2 versus 5.4±0.3 mL O2/100 mL) and the variation in small vein (20-60 µm) O2 saturation as determined by its coefficient of variation (=100×SD/mean) increased (5.5 versus 10.5). With 2 hours of reperfusion, the blood flow decrement was reduced and O2 consumption returned to the value in the contralateral cortex. Oxygen extraction remained elevated in the ischemic-reperfused area and the coefficient of variation of small vein O2 saturation increased further (17.3). CONCLUSIONS: These data indicated continued reduction of O2 supply/consumption balance with reperfusion. They also demonstrated many small regions of low oxygenation within the reperfused cortical region.

Effects of blockade of NMDA receptors on cerebral oxygen consumption during hyperosmolar BBB disruption in rats.

Hyperosmolar blood-brain barrier (BBB) disruption has been reported to increase cerebral O2 consumption. This study was performed to test whether blockade of N-methyl-d-aspartate (NMDA) receptor would affect cerebral O2 consumption during hyperosmolar BBB disruption. A competitive NMDA receptor antagonist CGS-19755 10mg/kg was injected iv 15min before intracarotid infusion of 25% mannitol. Twelve min after BBB disruption, the BBB transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid ((14)C-AIB) was measured. Regional cerebral blood flow (rCBF), regional arteriolar and venular O2 saturation (SaO2 and SvO2 respectively), and O2 consumption were determined using (14)C-iodoantipyrine autoradiography and cryomicrospectrophotometry in alternate slices of the brain tissue. The Ki of (14)C-AIB was markedly increased with hyperosmolar mannitol in both the control (5.8×) and the CGS treated rats (5.2×). With BBB disruption, the O2 consumption was significantly increased (+39%) only in the control but not in the CGS treated rats and was significantly lower (-29%) in the CGS treated than the control rats. The distribution of SvO2 was significantly shifted to the higher concentrations with CGS treatment. Our data demonstrated an increase of O2 consumption by hyperosmolar BBB disruption and attenuation of the increase with NMDA blockade without affecting the degree of BBB disruption.

Effects of cannabinoid receptor agonist WIN 55,212-2 on blood-brain barrier disruption in focal cerebral ischemia in rats.

This study was performed to investigate whether WIN 55,212-2 (WIN), a cannabinoid receptor agonist, could attenuate blood-brain barrier (BBB) disruption in focal cerebral ischemia in rats and whether the CB 1 receptor antagonist rimonabant could prevent this attenuation. A total of 0.3 or 1 mg/kg of WIN was injected intravenously before and after permanent middle cerebral artery (MCA) occlusion. Some animals were pretreated with rimonabant 2 mg/kg i.p. before receiving 0.3 mg/kg of WIN. At 1 h after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (K(i)) of (14)C-α-aminoisobutyric acid and the volume of dextran distribution. With MCA occlusion, K(i) increased in the ischemic cortex (IC) in all of the experimental groups. However, the K(i) of the IC of the WIN 0.3 and 1 mg/kg groups was lower (­46 and ­42%, respectively, p < 0.05) than that of the control group. With rimonabant pretreatment, the K(i) of the IC became higher ((+)88%, p < 0.05) than with WIN 0.3 mg/kg alone and similar to that of the control rats. The difference in the volume of dextran distribution between the IC and the contralateral cortex was significant in the control but not in the WIN-treated rats. With rimonabant pretreatment, however, the difference became significant. Our data demonstrated that WIN could attenuate BBB disruption in focal cerebral ischemia and this attenuation could be prevented with rimonabant. Our data suggest an involvement of CB(1) receptors in the regulation of BBB disruption in the early stage of stroke.