PubMed · 229515
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L T Landmesser. 1979. Competitive interactions between developing cholinergic neurones.. https://doi.org/10.1016/s0079-6123(08)64649-x
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The effects of Pa-1G, a phospholipase A(2) (PLA(2)) from the venom of the Australian king brown snake (Pseudechis australis) were determined on the release of acetylcholine, muscle resting membrane potential and motor nerve terminal action potential at mouse neuromuscular junction. Intracellular recording from endplate regions of mouse triangularis sterni nerve-muscle preparations revealed that Pa-1G (800 nM) significantly reduced the amplitude of endplate potentials within 10 min exposure. The quantal content of endplate potentials was decreased to 58+/-6% of control after 30 min exposure to 800 nM Pa-1G. The toxin also caused a partial depolarisation of mouse muscle fibres within 60 min exposure. Extracellular recording of action potentials at motor nerve terminals showed that Pa-1G reduced the waveforms associated with both sodium and potassium conductances. To investigate whether this was a direct or indirect effect of the toxin on these ionic currents, whole cell patch clamp experiments were performed using human neuroblastoma (SK-N-SH) cells and B82 mouse fibroblasts stably transfected with rKv1.2. Patch clamp recording experiments confirmed that potassium currents sensitive to alpha-dendrotoxin recorded from B82 cells and sodium currents in SK-N-SH cells were not affected by the toxin. Since neither facilitation of acetylcholine release at mouse neuromuscular junction nor depression of potassium currents in B82 cells has been observed, the apparent blockade of potassium currents at mouse motor nerve endings induced by the toxin is unlikely to be due to a selective block of potassium channels.
Following a brief description of the psychological construct 'divided attention', impairments in divided attention and related executive functions are discussed as the major variable in the development and manifestation of age- and dementia-associated cognitive impairments. Neuropsychological and functional imaging studies in humans have indicated that dorsolateral and ventrolateral prefrontal, cingulate, parietal and premotor cortical areas are involved in the mediation of dual task performance. Furthermore, reduced activity in these areas has been suggested to mediate age- and dementia-associated impairments in divided attention. Experimental studies in animals have provided strong support for the hypothesis that cholinergic projections terminating in all cortical areas and layers crucially mediate the performance in tasks that tax processing capacity and/or the allocation of processing resources to competing demands. This specification of the 'cholinergic hypothesis' is evaluated in light of recent critical accounts of the role of this system in the development of age- and dementia- related cognitive disorders. The converging animal experimental and human neuropathological, as well as neuropsychological, evidence indicates that decreases in the integrity of cortical cholinergic inputs represent a necessary, possibly even sufficient, neuronal process mediating the impairments in divided attention and the resulting, broad decline in cognitive functions.
We wanted to determine whether oxygen radicals open the mitochondrial ATP-dependent potassium channels (K(ATP)) during an ischemic period to reduce cell death and oxidant stress. Chick embryonic cardiomyocytes were used. Cell viability was quantified with propidium iodide (5 microM), and free radicals was measured using 2',7'-dichlorofluorescein diacetate. Preconditioning was produced by 10 min of simulated ischemia followed by 10 min of reoxygenation. Acetylcholine (1 mM), infused for 10 min instead of preconditioning, reduced cell death similarly (24 +/- 5%, n = 7 and 18 +/- 2%, n = 7, respectively, vs. controls, 49 +/- 6%, n = 8). In control series, 60 min of simulated ischemia and 3 h of reoxygenation generated free radicals more than 300% above the baseline (ischemia: 3.63 +/- 0.58, reoxygenation: 3.66 +/- 0.47, n = 8). Preconditioning and acetylcholine markedly attenuated the oxidant stress during simulated ischemia (1.18 +/- 0.41, n = 6 and 1.34 +/- 0.60, n = 7 vs. controls 3.63 +/- 0.58, n = 8) and re-oxygenation (1.23 +/- 0.36, n = 6 and 1.50 +/- 0.59, n = 7 vs. controls 3.66 +/- 0.47, n = 8). The protection of acetylcholine was abolished with pretreatment with the antioxidant thiol reductant 2-mercaptopropionyl glycine and posttreatment with 5-hydroxydecanoate, a selective mitochondrial K(ATP) channel antagonist (37 +/- 7%, n = 7). These results demonstrate that oxygen radicals open mitochondrial K(ATP) channels, which mediates the acetylcholine-induced preconditioning effect, and that stimulation of this signaling pathway attenuates oxidant stress.