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Notes: Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle produces a prolonged (〉3 months) elevation of Fos-like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Foslike immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6-OHDA-lesioned rats to determine the nature of Fos-immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6-OHDA lesion, expression of two Fos-related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated expression of these Fos-related antigens, suggesting that their induction after dopaminergic denervation is mediated by reduced activation of D2-like dopamine receptors. Western blot immunostaining using an antibody which recognizes the N-terminus of FosB indicated that the 43 and 45 kDa Fos-related antigens induced by dopaminergic denervation and chronic haloperidol administration may be related to a truncated from of FosB known as ΔFosB. Consistent with this proposal, retrograde tracing experiments confirmed that ΔFosB-like immunoreactivity in the deafferented striatum was located predominantly in striatopallidal neurons. Gel shift experiments demonstrated that elevated AP-1 binding activity in denervated striata contained FosB-like protein(s), suggesting that enhanced ΔFosB levels may mediate some of the effects of prolonged dopamine depletion on AP-1-regulated genes in striatopallidal neurons. In contrast, chronic administration of the D1-like receptor agonist CY 208–243 to 6-OHDA-lesioned rats dramatically enhanced ΔFosB-like immunoreactivity in striatal neurons projecting to the substantia nigra. Western blot immunostaining revealed that ΔFosB and, to a lesser extent, FosB are elevated by chronic D1-like agonist administration. Both the quantitative reverse transcriptase-polymerase chain reaction and the ribonuclease protection assay demonstrated that Δfos B mRNA levels were substantially enhanced in the denervated striatum by chronic D1-like agonist administration. Lastly, we examined the effects of chronic administration of D1-like and D2-like dopamine receptor agonists on striatal ΔFosB expression in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. In monkeys rendered Parkinsonian by MPTP, there was a modest increase in ΔFosB-like protein(s), while the development of dyskinesia produced by chronic D1-like agonist administration was accompanied by large increases in ΔFosB-like protein(s). In contrast, administration of the long-acting D2-like agonist cabergoline, which alleviated Parkinsonian symptoms without producing dyskinesia reduced ΔFosB levels to near normal. Taken together, these results demonstrate that chronic alterations in dopaminergic neurotransmission produce a persistent elevation of ΔFosB-like protein(s) in both the rodent and primate striatum.

Notes: [Auszug] We show here that transient forebrain ischemia selectively elevates levels of neuronal apoptosis inhibitory protein (NAIP) in rat neurons that are resistant to the injurious effects of this treatment. This observation suggests that increasing NAIP levels may confer protection against ischemic cell ...

Notes: Abstract The purpose of the study was to compare the role of Na ions in the damage caused by cardioplegic ischemia in fast (rat) and slow (pig) hearts. Changes in intracellular Na+ (Na+ i), high energy phosphates, and contractile function were assessed during ischemia (36°C) and reperfusion in KCl-arrested perfused hearts using31P-NMR and shift reagent (DyTTHA3−)-aided23Na-NMR spectroscopy. In the pig hearts the rates of decrease of phosphocreatine (PCr), ATP and intracellular pH (pHi) were 3–4 times slower than the rates observed in the rat hearts. In the pig hearts PCr was observable (∼10%) during first 80 min of the ischemic period (90 min). Comparable decreases in ATP (32.0±6 vs. 38±15% of initial) and pHi, (to 6.14±0.06 vs. 6.10±0.15) observed after 90 and 20 min ischemia in pig and rat hearts, respectively, were associated with a smaller Na+ i increase in the pig hearts (to 175±31%) than in the rat hearts (to 368±62%). This Na+ increase in the rat hearts preceded development of ischemic contracture (41±6 mmHg at 23.6±0.7 min) while no contracture was observed in pig hearts. Reperfusion of the rat hearts (at 30 min ischemia) was followed by partial recovery of PCr (44±3%) and Na+ i (234±69%) and poorer recovery of the pressure-rate product (PRP, 9±4%) and end-diastolic pressure (EDP, 72±5 mm Hg) compared to the pig hearts (PCr, 106±25%; Na+ i, 82±17%; PRP, 24±3%; EDP, 4.6±2.5 mmHg). The loss of function in the pig hearts was reversed by increasing Ca++ in the perfusate from 1 to 2.3 mM and resulted in a rise in both PRP and oxygen consumption rate, V(O2), from 24±3.3 to 64.5±5.8% and from 55±10 to 74±10% of the control levels, respectively. The PRP/ΔV(O2) ratio was halved in the post-ischemic pig hearts and returned to the pre-ischemic level following Ca++ stimulation. It is suggested that the higher stability of Na+ homeostasis to ischemic stress in the pig heart may result from: 1) a lower ratio of the rate of ATP hydrolysis to glycolytic ATP production; 2) differences in the kinetic properties of the Na+ transporters. Reduced Na+ accumulation during ischemia and reperfusion is benefical for metabolic and functional preservation of cardiomyocytes.