Is longer sevoflurane preconditioning neuroprotective in permanent focal cerebral ischemia?

Sevoflurane preconditioning has neuroprotective effects in the cerebral ischemia/reperfusion model. However, its influence on permanent cerebral ischemia remains unclear. In the present study, the rats were exposed to sevoflurane for 15, 30, 60, and 120 minutes, followed by induction of perma-nent cerebral ischemia. Results demonstrated that 30-and 60-minute sevoflurane preconditioning significantly reduced the infarct volume at 24 hours after cerebral ischemia, and 60-minute se-voflurane preconditioning additionally reduced the number of TUNEL-and caspase-3-positive cells in the ischemic penumbra. However, 120-minute sevoflurane preconditioning did not show evident neuroprotective effects. Moreover, 60-minute sevoflurane preconditioning significantly attenuated neurological deficits and infarct volume in rats at 4 days after cerebral ischemia. These findings in-dicated that 60-minute sevoflurane preconditioning can induce the best neuroprotective effects in rats with permanent cerebral ischemia through the inhibition of apoptosis.     

Vascular endothelial growth factor induced angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits

INTRODUCTIONAt present, ischemic cerebrovascular diseases are mainly treated bythrombolysis, anticoagulation and anti-platelet aggregation, which arethe traditional methods for prevention and treatment of thrombosisand vasodilatation, to ameliorate blood …     

Is thrombophilia a factor in the development of hemiplegic cerebral palsy?

A population-based study of children with hemiplegic cerebral palsy (CP) was performed to investigate whether thrombophilic tendencies are implicated in the aetiology of the condition. Thirty-eight children (23 males, 15 females; mean age 8.7 years, SD 4.1 years) with hemiplegic CP were ascertained. Twenty-seven children(18 males, nine females; mean age 8.4 years, SD 4.3) gave consent for inclusion. The non-study group comprised five males and six females; mean age 9.4 years, SD 4.1. In six children, seven thrombophilic 'abnormalities' were identified. Five of these abnormalities were of an equivocal nature and probably did not represent true clinical thrombophilia; reasons for this interpretation are discussed. Contrary to other published non-population-based studies, we have not shown an association between thrombophilia and hemiplegic CP. More studies, including maternal studies, are required to explore this complex subject further.     

Combination of dexanabinol and tempol in focal cerebral ischemia: is there a ceiling effect?

Because ischemic neuronal death is triggered by several parallel mechanisms, a combination of drugs active against individual death-promoting mechanisms may have synergistic effects. Dexanabinol is a noncompetitive NMDA antagonist with anti-inflammatory effects and tempol is a nitroxide antioxidant. Therefore, we explored whether their combined use results in smaller infarct volumes as compared with their individual administration. Rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given vehicle, dexanabinol alone, tempol alone, or a combination of dexanabinol and tempol (n = 13 per group) 1 h later. Five animals in each group were evaluated with a motor rating scale 24 h after PMCAO and the infarct volumes were then measured. The remaining animals were examined with motor and behavioral scales up to 30 days after PMCAO and their infarct volumes were then determined. Motor disability and water maze latencies at all time points examined and infarct volumes at days 1 and 30 were significantly reduced in all active treatment groups when compared with vehicle. However, no significant differences were observed between the active treatment groups. In conclusions, combination therapy with dexanabinol and tempol does not appear to have additional neuroprotective effects compared to those conferred by each agent alone even when administered at optimal timing and dosing. Therefore, a ceiling neuroprotective effect that is impossible to overcome may exist.     

Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition

Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is known to protect against cerebral ischemia. The effects of VPA on blood–brain barrier (BBB) disruption were investigated in rats subjected to transient middle cerebral artery occlusion (MCAO). Postischemic VPA treatment remarkably attenuated MCAO-induced BBB disruption and brain edema. Meanwhile, VPA significantly reduced MCAO-induced elevation of matrix metalloproteinase-9 (MMP-9), degradation of tight junction proteins, and nuclear translocation of nuclear factor-κB (NF-κB). Sodium butyrate, another HDAC inhibitor, mimicked these effects of VPA. Our findings suggest that BBB protection by VPA involves HDAC inhibition-mediated suppression of NF-κB activation, MMP-9 induction, and tight junction degradation.     

Is monochorionic twinning a risk factor for focal cortical dysgenesis?

OBJECTIVES: Various genetic and acquired factors have been proposed as being etiologically important in cortical dysgenesis. It has been suggested that fetal, developmental abnormalities may be induced by transient, circulatory instability in monochorionic twinning due to feto-fetal transfusions. We report the discordant occurrence of a malformation of cortical development in monozygotic, monochorionic twins, and discuss the findings and possible pathogenetic mechanisms. MATERIAL AND METHODS: The twins were females, 30 years of age, one of them suffering from uncontrolled localization-related epilepsy. Neurological deficits or mental retardation were not present. Genetic analysis, brain MRI, and a neuropsychological test battery were carried out. RESULTS: DNA analysis verified monozygocity. MRI showed a unilateral grey matter heterotopion and a contralateral temporal arachnoid cyst in the affected twin. Neuro-psychological assessment revealed no corresponding focal cognitive deficits, but an overall slightly lowered performance in the affected twin. CONCLUSION: Discordant affection of focal, cortical dysgenesis in monozygotic twins creates a particular opportunity to assess the consequences of such a disorder. The fact that only a mild generalized influence on cognitive functioning was demonstrated in this case, is possibly due to the plasticity of the fetal brain. According to current, obstetrical literature, the unique embryology of monochorionic twinning may predispose to vascular events in early fetal life. As ultrasound studies now indicate that a large proportion of pregnancies start out as twin products, we hypothesize that the "vanishing twin" syndrome and its potential hemodynamic hazard to the surviving fetus may be an etiological factor in malformations of cortical development, even in singletons.     

Effects of blockade of ionotropic glutamate receptors on blood–brain barrier disruption in focal cerebral ischemia

To determine whether blockade of ionotropic glutamate receptors such as NMDA or AMPA receptors would attenuate blood–brain barrier (BBB) disruption in focal cerebral ischemia, 15 min before middle cerebral artery (MCA) occlusion, CGS-19755 or NBQX was injected intraperitoneally in rats. At 1 h after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (K _i ) of ¹⁴C-α-aminoisobutyric acid and the volume of dextran distribution. With MCA occlusion, K _i was increased in the ischemic cortex (IC) (316%). CGS-19755 attenuated the increase in K _i in the IC (−46%), but NBQX did not significantly decrease it. The difference in the volume of dextran distribution between the IC and the contralateral cortex became insignificant with the blockade of NMDA or AMPA receptors. Our data demonstrated that blockade of NMDA or AMPA receptors could attenuate the BBB disruption in focal cerebral ischemia and suggest that ionotropic glutamate receptors are involved in part in BBB disruption.     

PDGFR-β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia

Although platelet-derived growth factors (PDGFs) and receptors (PDGFRs) are abundantly expressed in the central nervous system, their functions largely remain elusive. We investigated the role of PDGFR-β in tissue responses and functional recovery after photothrombolic middle cerebral artery occlusion (MCAO). In the normal adult mouse brain, PDGFR-β was mainly localized in neurons and in pericyte/vascular smooth muscle cells (PC/vSMCs). From 3 to 28 days after MCAO, postnatally induced systemic PDGFR-β knockout mice (Esr-KO) exhibited the delayed recovery of body weight and behavior, and larger infarction volume than controls. In Esr-KO, PC/vSMC coverage was decreased and vascular leakage of infused fluorescent-labeled albumin was extensive within the ischemic lesion, but not in the uninjured cerebral cortex. Angiogenesis levels were comparable between Esr-KO and controls. In another PDGFR-β conditional KO mouse (Nestin-KO), PDGFR-β was deleted in neurons and astrocytes from embryonic day 10.5, but was preserved in PC/vSMCs. After MCAO, vascular leakage and infarction volume in Nestin-KO were worse than controls, but partly improved compared with Esr-KO. Astroglial scar formation in both Esr-KO and Nestin-KO was similarly reduced compared with controls after MCAO. These data suggested that PDGFR-β signaling is crucial for neuroprotection, endogenous tissue repair, and functional recovery after stroke by targeting neurons, PC/vSMCs, and astrocytes.     

Behavioural inhibition: Is it a risk factor for anxiety?

Abstract

Behavioural inhibition is a stable temperamental trait that is identifiable during infancy and toddlerhood and is characterized by fearful reactivity to novelty. Children identified as behaviourally inhibited have been shown to be at increased risk for developing anxiety disorders such as social phobia. The current review addresses the link between behavioural inhibition and the risk for developing anxiety disorders. Research suggests that this risk may be modulated by a number of extrinsic and intrinsic factors. Extrinsic factors include particular parental beliefs, parenting styles, and childrearing contexts. Intrinsic factors include executive function capacities such as attention bias, attention shifting, inhibitory control, and self-monitoring. In the present paper we review the contribution of these factors to the development of anxiety in behaviourally inhibited children.     

Ischemic postconditioning in cerebral ischemia: Differences between the immature and mature brain?

Ischemic postconditioning (postC), defined as serial mechanical interruptions of blood flow at reperfusion, effectively reduces myocardial infarct size in all species tested so far, including humans. In the brain, ischemic postC leads to controversial results regardless of variations in factors such as onset time of beginning, the duration of ischemia and/or reperfusion, and the number of cycles of occlusion/reperfusion. Thus, many major issues remain to be resolved regarding its protective effects. Future studies should aim to identify the parameters that yield the strongest protection, as well as to understand why the efficacy of ischemic postC differs between models. This review will focus on initial hemodynamic changes and their consequences, and on specific features such as NO-dependent vascular tone and/or prolonged acidosis in cerebral ischemia-reperfusion in order to better understand the dynamics of ischemic postC in the developing brain.     

Blood–brain barrier breakdown involves four distinct stages of vascular damage in various models of experimental focal cerebral ischemia

Ischemic stroke not only impairs neuronal function but also affects the cerebral vasculature as indicated by loss of blood–brain barrier (BBB) integrity. Therefore, therapeutical recanalization includes an enhanced risk for hemorrhagic transformation and bleeding, traditionally attributed to a ‘reperfusion injury''. To investigate the mechanisms underlying ischemia-/reperfusion-related BBB opening, we applied multiple immunofluorescence labeling and electron microscopy in a rat model of thromboembolic stroke as well as mouse models of permanent and transient focal cerebral ischemia. In these models, areas exhibiting BBB breakdown were identified by extravasation of intravenously administered fluorescein isothiocyanate (FITC)-albumin. After 24 hours, expression of markers for tight and adherens junctions in areas of FITC-albumin leakage consistently remained unaltered in the applied models. However, lectin staining with isolectin B4 indicated structural alterations in the endothelium, which were confirmed by electron microscopy. While ultrastructural alterations in endothelial cells did not differ between the applied models including the reperfusion scenario, we regularly identified vascular alterations, which we propose to reflect four distinct stages of BBB breakdown with ultimate loss of endothelial cells. Therefore, our data strongly suggest that ischemia-related BBB failure is predominantly caused by endothelial degeneration. Thus, protecting endothelial cells may represent a promising therapeutical approach in addition to the established recanalizing strategies.     

Is methamphetamine abuse a risk factor in parkinsonism?

Parkinsons disease (PD) is a neurodegenerative disorder with increased incidence in individuals beyond 50 years of age. The etiology of PD is currently not known, but it appears that environmental factors may play an important role. The molecular basis of PD is the nearly complete loss of the neurotransmitter dopamine (DA) in the basal ganglia (caudate/putamen). The decrease in dopamine levels is the result of degeneration of dopamine-containing neurons in the substantia nigra. This biochemical deficit in the nigrostriatal pathway leads to the emergence of motor impairments typical of PD. Methamphetamine (METH) is a psychostimulant drug with increasing use in certain segments of the population in the United States and worldwide. In experimental animal models and human studies, METH administration has been shown to decrease markers of dopaminergic neuron terminal integrity in the basal ganglia. A long-standing question has been whether the reductions in dopaminergic markers induced by METH constitute degenerative changes or reflect drug-induced modulation. Resolving this question is important because the irreversible loss of dopaminergic function may increase the likelihood of Parkinsonism with advancing age.     

Is interlimb coordination during walking preserved in children with cerebral palsy?

Arm movements during gait in children with cerebral palsy (CP) are altered compared to typically developing children (TD). We investigated whether these changes in arm movements alter interlimb coordination in CP gait. 3D gait analysis was performed in CP (diplegia [DI]: N = 15 and hemiplegia [HE]: N = 11) and TD (N = 24) children at preferred and fast walking speeds. Mean Relative Phase (MRP, i.e. mean over the gait cycle of the Continuous Relative Phase or CRP) was calculated as a measure of coordination, standard deviation of CRP was used as a measure of coordinative stability, and the sign of MRP indicated which limb was leading (for all pair combinations of the four limbs). In HE, coordination was significantly altered, less stable and a different leading limb was found compared to TD whenever the most affected arm was included in the studied limb pair. In DI, coordination deteriorated significantly when any of the two legs was included in the studied limb pair, and coordinative stability was significantly affected when any of the two arms was included. In almost all limb pair combinations, a different limb was leading in DI compared to TD. Increasing walking speed significantly improved coordination and coordinative stability of several limb pairs in DI. Coordination and limb-leading deficits were mostly linked to the affected limb. The compensating (non-affected) arm primarily affected coordinative stability, which underlines the importance of active arm movements in HE. Increasing walking speed may be used to improve interlimb coordination in DI.