Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis.

The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies suggested the linkage of TSC to altered cerebral blood flow and metabolic dysfunction. We previously reported a significant elevation in cerebral blood flow in an animal model of TSC and autism of young Eker rats.

Leucine Reduced Blood-Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion.

A disruption of the blood-brain barrier (BBB) is a crucial pathophysiological change that can impact the outcome of a stroke. Ribosomal protein S6 (S6) and protein kinase B (Akt) play significant roles in early cerebral ischemia-reperfusion injury. Studies have suggested that branched-chain amino acids (BCAAs) may have neuroprotective properties for spinal cord or brain injuries.

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia-Reperfusion With Increased Blood-Brain Barrier Disruption.

It has been reported that the mechanistic target of rapamycin (mTOR) pathway is involved in cerebral ischemia-reperfusion injury. One of the important pathological changes during reperfusion after cerebral ischemia is disruption of blood-brain barrier (BBB). Rapamycin, a first-generation mTOR inhibitor, produces divergent effects on neuronal survival and alteration in BBB disruption.

Inhibition of serum and glucocorticoid regulated kinases by GSK650394 reduced infarct size in early cerebral ischemia-reperfusion with decreased BBB disruption.

Blood-brain barrier (BBB) disruption is one of the most important pathological changes following cerebral ischemia-reperfusion. We tested whether inhibition of the serum and glucocorticoid regulated kinase 1 (SGK1) would decrease BBB disruption and contribute to decreasing infarct size in the first few hours of cerebral ischemia-reperfusion within the thrombolysis therapy time window. After transient middle cerebral artery occlusion (MCAO), an SGK1 inhibitor GSK650394, or vehicle was administered into the lateral ventricle of rats.

Adhesion molecule L1 inhibition increases infarct size in cerebral ischemia-reperfusion without change in blood-brain barrier disruption.

Objective: Neural cell adhesion molecule L1CAM (L1) is involved in neuroprotection. To investigate a possible neuroprotective effect of L1 during ischemia, we determined whether blocking L1 with an antagonistic antibody would worsen the outcome of focal cerebral ischemia-reperfusion and increase blood-brain barrier (BBB) disruption.

Methods: Transient middle cerebral artery occlusion (MCAO) was performed in anesthetized rats.

Lysophosphatidic acid increased infarct size in the early stage of cerebral ischemia-reperfusion with increased BBB permeability.

Background: We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling.

Material And Methods: Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected.

Lysophosphatidic Acid Reduces Microregional Oxygen Supply/Consumption Balance after Cerebral Ischemia-Reperfusion.

Background: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system.

Objective: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O2 supply/consumption balance after cerebral ischemia-reperfusion.

Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion).

Improvement in Microregional Oxygen Supply/Consumption Balance and Infarct Size After Cerebral Ischemia-Reperfusion With Inhibition of p70 Ribosomal S6 Kinase (S6K1).

Background: We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O supply/consumption balance after cerebral ischemia-reperfusion.

Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 hour and reperfusion for 2 hours with or without PF-4708671 (S6K1 inhibitor, 75 mg/kg, 15 minutes after blockade). Regional cerebral blood flow was determined using a C-iodoantipyrine autoradiographic technique.

Inhibition of p70 ribosomal S6 kinase 1 (S6K1) by PF-4708671 decreased infarct size in early cerebral ischemia-reperfusion with decreased BBB permeability.

It is not clear whether inhibition of p70 ribosomal S6 kinase 1 (S6K1) is neuroprotective in cerebral ischemia-reperfusion. Decreasing blood-brain barrier (BBB) disruption has been associated with a better neuronal outcome in cerebral ischemia. We hypothesized that inhibition of S6K1 would decrease BBB disruption and infarct size in the early stage of cerebral ischemia-reperfusion.

Activation of Akt by SC79 decreased cerebral infarct in early cerebral ischemia-reperfusion despite increased BBB disruption.

Activation of Akt has been suggested to produce neuronal protection in cerebral ischemia. Decreasing blood-brain barrier (BBB) disruption has been associated with a better neuronal outcome in cerebral ischemia. We hypothesized that activation of Akt would decrease BBB disruption and contribute to decreasing the size of infarct in the early stage of cerebral ischemia-reperfusion within the therapeutic window.

Akt activation improves microregional oxygen supply/consumption balance after cerebral ischemia-reperfusion.

There have been reports that activation of Akt may provide neuroprotection after cerebral ischemia-reperfusion. We tested the hypothesis that activation of Akt would decrease infarct size and improve microregional O supply/consumption balance after cerebral ischemia-reperfusion. This hypothesis was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without SC-79 (Akt activator, 0.

Rapamycin decreased blood-brain barrier permeability in control but not in diabetic rats in early cerebral ischemia.

Diabetes causes functional and structural changes in blood-brain barrier (BBB). The mammalian target of rapamycin (mTOR) has been associated with glucose metabolism, diabetes, and altering BBB permeability. Since there is only a narrow therapeutic window (3h) for stroke victims, it is important to investigate BBB disruption in the early stage of cerebral ischemia.

Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia.

One of the important factors altering the degree of blood-brain barrier (BBB) disruption in cerebral ischemia is the anesthetic used. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be involved in modulating BBB permeability and in isoflurane induced neuroprotection. This study was performed to compare the degree of BBB disruption in focal cerebral ischemia under isoflurane vs pentobarbital anesthesia and to determine whether inhibition of PI3K/Akt would affect the disruption in the early stage of focal cerebral ischemia.

Hypoxic Preconditioning Increases Blood-Brain Barrier Disruption in the Early Stages of Cerebral Ischemia.

Even though hypoxic preconditioning has been reported to produce neuroprotection, its effect on blood-brain barrier (BBB) disruption in the early stages of cerebral ischemia within the therapeutic window is not clear. Since hypoxic preconditioning increases expression of vascular endothelial growth factor (VEGF) that modulates vascular permeability, the effects of hypoxic preconditioning and VEGF on BBB permeability were investigated after one hour of focal cerebral ischemia. Rats were exposed to 8% of oxygen for two hours or room air and then 24 hours later, permanent middle cerebral artery (MCA) occlusion was performed.

Effects of rapamycin pretreatment on blood-brain barrier disruption in cerebral ischemia-reperfusion.

The mammalian target of rapamycin (mTOR) pathway is essential in neuronal survival and repair in cerebral ischemia. Decreases in blood-brain barrier (BBB) disruption are associated with a decrease in neuronal damage in cerebral ischemia. This study was performed to investigate how pre-inhibition of the mTOR pathway with rapamycin would affect BBB disruption and the size of the infarcted cortical area in the early stage of focal cerebral ischemia-reperfusion using quantitative analysis of BBB disruption.

Inhibition of neuronal nitric oxide synthase improves microregional O balance in cerebral ischemia-reperfusion.

Objectives Return of regional cerebral blood flow (rCBF) in focal cerebral ischaemia may not ensure proper distribution of blood flow to meet metabolic demand. This study was performed to determine how inhibition of neuronal nitric oxide synthase (NOS) during ischaemia-reperfusion would affect microregional O supply/consumption balances and their variation. Methods Twenty minutes before middle cerebral artery (MCA) occlusion, a NOS inhibitor 7-nitroindazole (7-NI) 50 mg/kg ip (7-NI group) or vehicle (control group) was administered.

Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis.

Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated.

Local O2 Balance in Cerebral Ischemia-Reperfusion Improved during Pentobarbital Compared with Isoflurane Anesthesia.

Background: Most anesthetics affect cerebral blood flow and metabolism. We compared microregional O2 balance in cerebral ischemia-reperfusion during pentobarbital and isoflurane anesthesia.

Methods: After 1 hour of middle cerebral artery occlusion and a 2-hour reperfusion under isoflurane (1.

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.

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).

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.

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.

Reduced effect of stimulation of AMPA receptors on cerebral O₂ consumption in a rat model of autism.

Previous work demonstrated that basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activity did not contribute to the elevated regional cerebral O₂ consumption in the brains of Eker rat (an autism-tuberous sclerosis model). We tested the hypothesis that increased stimulation of AMPA receptors also would not augment cerebral O₂ consumption in the Eker rat. Three cortical sites were prepared for administration of saline, 10⁻⁴ and 10⁻³ M AMPA in young (4 weeks) male control Long Evans and Eker rats (70-100 g).

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.

The effects of dexmedetomidine on regional cerebral blood flow and oxygen consumption during severe hemorrhagic hypotension in rats.

Background: We performed this study to determine how dexmedetomidine would affect regional cerebral blood flow (rCBF) and microregional O(2) consumption during nonhemorrhagic normovolemia and during severe hemorrhagic hypotension in rats.

Methods: Forty-eight male rats were anesthetized with isoflurane and their lungs were mechanically ventilated. Half of the rats were bled to reach a mean arterial blood pressure of 40 to 45 mm Hg and were maintained at this level for at least 30 minutes before rCBF or microregional arterial oxygen saturation (Sao(2)) and venous oxygen saturation (Svo(2)) were determined.