Denervation recent

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

The role of the sympathetic nervous system in renal injury, end-stage renal disease, and renovascular hypertension are discussed through a literature review accompanying sympathetic nerve mechanisms in hypertension and obesity. Relevant studies of sympathetic nerve activity and 32-adrenoceptor polymorphism might contribute to the onset and maintenance of renal injury in healthy subjects and in patients with chronic heart failure and cardiovascular events in ESRD patients. A better understanding of the relationships of sympathetic nerve activity with renal injury might help clinical implications (treatment) for renal injury in hypertensive patients and hypertension in patients with ESRD. Recently, the role of denervation of renal sympathetic nerve in refractory hypertension has been examined and showed its efficacy in humans. The outcome from the study have not been established, but a number of animal studies show theoretical benefits for those patients in the acute phase. Further studies are needed to clarify the relationships between the sympathetic nerve activity and renal injury. 

Substances or tissue activators, such as histamine, 5-hydroxytryp-tamine, and acetylcholine, which are released in damaged tissue can stimulate the adrenal when injected directly into the adrenal blood supply. Early experiments in denervated limbs in rats suggested that the ascorbic acid depletion of the rat adrenal following injury in the isolated part was due to a humoral agent (Gl), and recent experiments show that 5-hydroxytryptamine has a direct stimulatory effect on aldosterone secretion (J7). 

The fatty acid composition of muscle lipids may show quantitative alterations in diseased muscle. Thus lecithin isolated from human dystrophic muscle had an increased amount of oleic but diminished linoleic acid (Tl). Changes have been recorded also in the fatty acid composition of lecithin from denervated muscle (PI). Recently it has been reported (K16) that the fatty acid pattern of muscle phosphatides from patients with the autosomal dominant form of myotonia congenita differed markedly from that of the autosomal recessive form and from the normal. Tani and his co-workers (F7) have made a detailed study of the phospholipids of normal and dystrophic mouse tissues. In normal mice phosphatidylcholine and phosphatidylethanolamine from skeletal and heart muscles had a very high content of 20-22-carbon polyunsaturated acids, in comparison with those for other tissues the most abundant was docosahexaenoic acid. In dystrophic mice there was a sharp decrease in the proportion of docosahexaenoic acid in the phosphoglycerides from skeletal and heart muscles, suggesting the likelihood of important alterations in muscle membranes. Somewhat similar studies have been reported by Owens (05), who also observed a fall in the proportion of docosahexaenoic acid, mainly in the phosphatidylcholine -j- choline plasmalogen fraction. 

Recent isotope incorporation studies by a number of workers have indicated increased turnover of muscle membrane lipids following denervation. These include increased incorporation of labeled phosphate and glycerol into glycerophosphatides (B17), increased turnover of... 

The first step in protein metabolism in muscle is the uptake of amino acids from the blood by the fibers, via the extracellular space. Experiments with injected amino acids and with isolated muscle preparations by many workers have demonstrated that muscle fibers can accumulate amino acids from the medium. Experiments with a-aminoisobutyric acid, a nonmetabolizable amino acid, have been particularly useful in enabling accumulation to be studied independently of incorporation of the amino acid into protein. An increased accumulation of amino acids has been observed in the dystrophic mouse (B3), in vitamin E deficiency (D4), and in denervated muscle (D4). The authors of the last-mentioned observation concluded from their evidence that the increased accumulation was associated with increased active transport into the muscle cells, not with a change in passive permeability of the membranes. Nichoalds et al. (Nl) found that puromycin, which abolished protein synthesis, had no effect upon the accumulation of glycine- C by control or vitamin E-deficient muscle. More recently, Goldberg and Goodman (G4) observed a decrease in the accumulation of a-aminoisobutyric acid by soleus and plantaris muscles within 3 hours of denervation subsequently. 

These tracers compete with endogenous noradrenalin for transport into pre-synaptic nerve terminals via the neuronal uptake-1 transport system. Once within the neuron, these tracers are not susceptible to metabolism and serve as markers of sympathetic innervation. Recent studies show decreased retention of ["C]HED in patients after cardiac transplant, consistent with heart denervation (Schwaiger et al., 1991). With time, some sympathetic reinnervation occurred particularly in the antero-septal regions of the heart. This correlates with recovery of the sensation of angina pectoris in these patients (Stark et al.,... 

Recently, our laboratory has utilized an improved extraction procedure for NGF (Zettler et al., 1995) to examine the effect of surgical denervation on its concentration within the mesenteric artery. The high levels of NGF present were reduced by denervation to approximately 20% of control levels. By assaying NGF within the adventitia and media separately, it was possible to demonstrate that the loss of NGF was associated only with the loss of nerve fibres within the adventitia. Furthermore, the discrepancy with the studies described above could be explained by the ability of the new extraction procedure to free large amounts of NGF bound to tissue components (such as trkA receptors) prior to assay (Liu, Reid, Bridges and Rush, unpublished observations). 

Throughout this century, many techniques have been used in an attempt to discover the mechanisms of limb regeneration—denervation, transplantation of blastemas to ectopic sites, organ culture, radiolabeling, gel electrophoresis, administration of compounds, such as retinoic acid, and so forth. However, recently three technical advances have been made that are certain to have an important influence on future discoveries. 

A much-studied respiratory depressant effect of hypoxia that is either directly or indirectly mediated by the CNS has been termed hypoxic ventilatory decline. That the ventilatory deeline with arterial hypoxia in carotid sinus nerve (CSN) denervated anesthetized eats with maintained arterial Pco2 could be reversed by electrical stimulation of the eut CSN suggests that the CSN input maintained ventilation with eoneomitant central nervous system (CNS) hypoxic depression (19a). This evidenee also suggests that hypoxic CNS inhibition is an active process (see later. Refs. 2,4,11). In adult humans and some animals, when isocapnic hypoxia is produced in a square-wave fashion, the initial enhancement of respiratory output is followed, in about 5-7 min, by a decline to approximately 50% of the peak level (20-22). The phenomenon is best observed in the imanaesthetized state, but may be seen in anesthetized animals as well. It is far more prominent in the early neonate (1-5 days in humans) where the decline in respiratory output may be to baseline or below the initial level of respiratory output. Recent studies in the neonate have demonstrated a significant genetic variation to expression of this phenomenon (23). 

Figure 1.1 (a-e) Recent denervation without innervation, evidenced by small dark angular muscle fibers (a,b) amyotrophic lateral sclerosis ... 

This is our hypothetical concept of only partially impaired, incomplete loss of neural influence, especially of molecular neurotrophic factors, some of which are still able to be produced from crippled but alive motor neurons. Our putative "dysinnervation" phenomenon can be conceptualized as having some aspects similar to a persistence of the early stages of ordinary "recent denervation," to which it appears histochemically similar. 

Recent denervation without reinnervation compared to type-2 fiber atrophy... 

When slightly to moderately evolved, recent denervation without reinnervation (Figure l.la-e) is manifest (in transversely cut muscle fibers) as small... 

Both type-2 fiber atrophy and recent denervation... 

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