Abstract:Within the CNS and under normal conditions, nitric oxide ('NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that 'No is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances N0 synthesis may be excessive and N0 may become neurotoxic. Excessive glutamatereceptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both 'No and superoxide (02') and hence peroxynitrite (ONOO ) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of 'No, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of 'No neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADPribose) synthetase. Possible mechanisms whereby ONOO impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining the sensitivity of cells to ONOOproduction. lt is concluded that neurotoxicity elicited by excessive 'NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte survival, these molecules may diffuse out to cause mitochondrial damage, and possibly cell death, to other cells, such as neurones, in close proximity. Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis. In other conditions, such as ischaemia, increased availability of glutamate may lead to an activation of a calcium-dependent nitric oxide synthase associated with neurones. Such increased/inappropriate NO formation may contribute to energy depletion and neuronal cell death. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic strategies are proposed.

This study investigated the prevalence of transformative experiences, antecedents of transformative experience, and the relation between transformative experience and deep-level learning (conceptual change and transfer) for high school biology students (N = 166). Results suggested that the high school students in our sample typically engaged in low levels of transformative experience with respect to biology, but those students who strongly identified with science and who endorsed a mastery goal orientation were more likely to report engagement in higher levels of transformative experience. Furthermore, a higher level of engagement in transformative experience was positively associated with (a) conceptual change in understanding the concept of natural selection, but not inheritance, at the post-and follow-up assessments and (b) transfer at the follow-up assessment. According to Jackson (1986), there are two enduring outlooks in education, the mimetic, which focuses on transmitting predetermined and measurable information to students, and the transformative, which focuses on the transformation of qualities such as values, attitudes, and perceptions. Unfortunately, the majority of our efforts for educating children

Manganese-salen complexes (Mn-Salen), including EUK-8 [manganese N,N'-bis(salicylidene)ethylenediamine chloride] and EUK-134 [manganese 3-methoxy N,N'-bis(salicylidene)ethylenediamine chloride], have been reported to possess combined superoxide dismutase (SOD) and catalase mimetic functions. Because of this SOD/catalase mimicry, EUK-8 and EUK-134 have been investigated as possible therapeutic agents in neurological disorders resulting from oxidative stress, including Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis. These actions have been explained by the ability of the Mn-Salen to remove deleterious superoxide (O(2)(-)) and H(2)O(2). However, in addition to oxidative stress, cells in models for neurodegenerative diseases may also be subjected to damage from reactive nitrogen oxides (nitrosative stress), resulting from elevated levels of NO and sister compounds, including peroxynitrite (ONOO(-)). We have been examining the interaction of EUK-8 and EUK-134 with NO and ONOO(-). We find that in the presence of a per-species (H(2)O(2), ONOO(-), peracetate and persulphate), the Mn-Salen complexes are oxidized to the corresponding oxo-species (oxoMn-Salen). OxoMn-Salens are potent oxidants, and we demonstrate that they can rapidly oxidize NO to NO(2) and also oxidize nitrite (NO(2)(-) to nitrate (NO(2)(-)). Thus these Mn-Salens have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O(2)(-), H(2)O(2), ONOO(-) and NO to benign species: O(2), H(2)O, NO(2)(-) and NO(3)(-).