Pharmacological Preconditioning with GYKI 52466: A Prophylactic Approach to Neuroprotection.

Some toxins and drugs can trigger lasting neuroprotective mechanisms that enable neurons to resist a subsequent severe insult. This "pharmacological preconditioning" has far-reaching implications for conditions in which blood flow to the brain is interrupted. We have previously shown that in vitro preconditioning with the AMPA receptor antagonist GYKI 52466 induces tolerance to kainic acid (KA) toxicity in hippocampus. This effect persists well after washout of the drug and may be mediated via inverse agonism of G-protein coupled receptors (GPCRs). Given the amplifying nature of metabotropic modulation, we hypothesized that GYKI 52466 may be effective in reducing seizure severity at doses well below those normally associated with adverse side effects. Here we report that pharmacological preconditioning with low-dose GYKI imparts a significant protection against KA-induced seizures in vivo. GYKI (3 mg/kg, s.c.), 90-180 min prior to high-dose KA, markedly reduced seizure scores, virtually abolished all level 3 and level 4 seizures, and completely suppressed KA-induced hippocampal c-FOS expression. In addition, preconditioned animals exhibited significant reductions in high frequency/high amplitude spiking and ECoG power in the delta, theta, alpha, and beta bands during KA. Adverse behaviors often associated with higher doses of GYKI were not evident during preconditioning. The fact that GYKI is effective at doses well-below, and at pre-administration intervals well-beyond previous studies, suggests that a classical blockade of ionotropic AMPA receptors does not underlie anticonvulsant effects. Low-dose GYKI preconditioning may represent a novel, prophylactic strategy for neuroprotection in a field almost completely devoid of effective pharmaceuticals

He huarahi ako : pathways to learning : the academic and cultural self-efficiency of Maori student teachers : a thesis presented in partial fulfilment of the requirements for the degree of Master of Philosophy in Maori Studies at Massey University, Palmerston North, New Zealand

The present study sought to investigate the factors that affect Māori student teachers academic and cultural self-efficacy in a teacher education programme. Identifying these factors is considered important for developing appropriate teacher education programmes to better provide for this increasing population of student teachers. The target sample goup are Māori student teachers who are enrolled in the general teacher education programme at Te Kupenga o te Mātauranga. Underpinning the development of these student teachers lies an expectation that they will provide Māori input in general education schools and programmes, based mainly on the fact that they are Māori. Ensuring that these student teachers are therefore culturally competent to do so is important it success is to be achieved tor themselves personally, for Māori and for New Zealand society. A framework has been developed to assist in examining important Māori concepts in relation to teacher education. The development in Kura Kaupapa Māori teacher education programmes has meant that the pool of more culturally competent Māori student teachers has been absorbed into those programmes. There remains, however, a commitment to Māori student teachers in general teacher education to continue achievement in both Te Ao Māori (the Māori world) and Te Ao Whānaui (the wider world). This study analysed two kinds of data; a survey (of 24 student teachers) and formal interviews (of four of the survey participants). Quantitative analysis were integrated with qualitative data from the interviews. In identifying factors that affect the academic and cultural self-efficacy of these student teachers it became clear that their sense of collective efficacy was highly influential in both contexts. In the academic context however, it was given lesser emphasis than in the cultural context, as work in the academic context in the main required them to work independently. These student teachers were more inclined to work in groups, to support each others learning and to discuss tasks amongst themselves. These factors tended to develop in them a stronger sense of collective efficacy. Student teachers who had come straight from school with formal qualifications (Bursary) generally displayed higher levels of academic self-efficacy. However, many had entered college with other qualifications such as work experience or suitability for teaching and tended to have lower levels of self-efficacy in the academic context. While the majority of these student teachers claimed to be capable learners, most also claimed the need to develop skills and strategies that could help them in both the academic and cultural contexts. Achievement in Te Ao Māori (the Māori world) was for all of these student teachers a key issue. Yet, most expressed quite low levels of self-efficacy in this context. In particular, these low levels of self-efficacy were related to their competency in Te Reo Māori and Tikanga. Having high self-efficacy is said to provide higher levels of effort and perseverance in activities (Bandura, 1986). Despite having generally lower levels of self-efficacy for Te Reo Māori and Tikanga, these student teachers showed persistence and motivation in learning about their own culture. Te Reo Māori. Tikanga and Whānau proved to be key sources in the development of these student teachers' cultural self-efficacy

Investigating the Mechanisms of Pharmacological Preconditioning In Vitro and In Vivo

Preconditioning involves the induction of endogenous protective mechanisms to prevent damage due to subsequent insult. The acute window of protection could provide a neuroprotective strategy for patients with a known risk of ischemia, such as those undergoing heart surgery, for which there are currently no such prophylactic options available. The aim of this thesis was to identify contributing factors to the mechanism of preconditioning protection. By understanding the mechanisms behind the protective effect, it may be possible to develop safe and effective pharmaceuticals to induce acute protection for clinical use. Previous experiments in our lab had demonstrated in vitro preconditioning protection induced by high potassium (Butler, 2008), kainic acid (Hesp et al., 2004) and GYKI-52466 (Hesp et al., 2004). Using the hippocampal slice preparation and electrophysiological recordings it was found that exposure to kainic acid (500 nM) was the most effective preconditioning stimulus against the suppression of evoked field responses during strong excitotoxic insult (p < 0.05). Using this model, the potential contribution of Na+K+-ATPase as an effector of preconditioning was investigated. Na+K+-ATPase is important for maintaining ionic homeostasis by actively extruding Na+, so an up-regulation in its pumping capacity could potentially cause a resistance to depolarising insult. Following kainic acid preconditioning, Na+K+-ATPase activity was elevated in hippocampal slices at the time point when an excitotoxic challenge would normally be administered (p < 0.01). A subset of slices was tested using electrophysiology and a corresponding resistance to excitotoxic insult was found. Interestingly, this preconditioning induced increase was not observed in cortical slices (p = 0.640). Overall, these experiments did support a contribution of Na+K+-ATPase regulation to preconditioning protection in the hippocampus, an area of the brain known to be particularly sensitive to excitotoxic insult

Investigating the Mechanisms of Pharmacological Preconditioning In Vitro and In Vivo

Preconditioning involves the induction of endogenous protective mechanisms to prevent damage due to subsequent insult. The acute window of protection could provide a neuroprotective strategy for patients with a known risk of ischemia, such as those undergoing heart surgery, for which there are currently no such prophylactic options available. The aim of this thesis was to identify contributing factors to the mechanism of preconditioning protection. By understanding the mechanisms behind the protective effect, it may be possible to develop safe and effective pharmaceuticals to induce acute protection for clinical use. Previous experiments in our lab had demonstrated in vitro preconditioning protection induced by high potassium (Butler, 2008), kainic acid (Hesp et al., 2004) and GYKI-52466 (Hesp et al., 2004). Using the hippocampal slice preparation and electrophysiological recordings it was found that exposure to kainic acid (500 nM) was the most effective preconditioning stimulus against the suppression of evoked field responses during strong excitotoxic insult (p < 0.05). Using this model, the potential contribution of Na+K+-ATPase as an effector of preconditioning was investigated. Na+K+-ATPase is important for maintaining ionic homeostasis by actively extruding Na+, so an up-regulation in its pumping capacity could potentially cause a resistance to depolarising insult. Following kainic acid preconditioning, Na+K+-ATPase activity was elevated in hippocampal slices at the time point when an excitotoxic challenge would normally be administered (p < 0.01). A subset of slices was tested using electrophysiology and a corresponding resistance to excitotoxic insult was found. Interestingly, this preconditioning induced increase was not observed in cortical slices (p = 0.640). Overall, these experiments did support a contribution of Na+K+-ATPase regulation to preconditioning protection in the hippocampus, an area of the brain known to be particularly sensitive to excitotoxic insult

Potentiation effect of the AMPK activator A-769662 on cardiac myocytes metabolism and survival

Abstract 286 van Poster session 2 Frontiers in CardioVascular Biology, London 30th March – 1st April 2012 Second Congress of the ESC Council on Basic Cardiovascular Science