Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796779
Title: An experimental model of porphyria
Author: Odber, Josephine
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1992
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Abstract:
1. The porphyrias are a group of disorders of haem metabolism, due to an enzymatic defect in the haem biosynthetic pathway. Two current hypotheses regarding the underlying causes of the neuropathy of the acute type of porphyria were examined. Firstly, are the haem precursors d-aminolaevulinic acid (ALA) and porphobilinogen (PBG) neurotoxic? Secondly, is acute porphyric neuropathy a consequence of a reduction in essential haemoproteins? 2. The responses of a variety of in vitro rabbit nerve/muscle preparations, whose responses are mediated by different neurotransmitters, were unaffected by ALA in concentrations ranging from 1muM. to 10mM. In isolated nerve/muscle preparations taken from rats that had received porphyrinogenic drug treatment, which disrupted haem biosynthesis, 10nM. to 300muM. ALA did not alter the responses of the muscles to electrical field stimulation of their intrinsic nerves. 3.30muM. to 1mM. PBG did not significantly alter the response of the rat anococcygeus muscle to electrical field stimulation of the intrinsic inhibitory nerves. 4. The results of these experiments provide no evidence that ALA or PBG are neurotoxic. 5. In the second group of experiments the porphyrinogenic drugs (succinylacetone; allylisopropylacetamide; DDC and its 4-ethyl analogue 4-ethyl DDC; phenobarbitone; lead) were employed, in various combinations, for periods ranging from 3 to 44 days, in an attempt to produce a haem deficiency neuropathy, in rats, by inhibiting haem synthesis. 6. A range of rat in vitro nerve/muscle preparations were examined, the responses of which are mediated by different neurotransmitters, one of which, the nitrergically-mediated inhibitory response of the anococcygeus muscle results from activation of a cytosolic haemoprotein, guanylate cyclase. 7. The results of this group of experiments provide no evidence that the porphyrinogenic compounds employed, in this study, reduce essential haemoproteins to levels where a neuropathy ensues. 8. The third group of experiments examined liver, blood and brain haemoproteins, following porphyrinogenic drug treatment for periods ranging between 14 and 44 days. Hepatic respiratory cytochrome levels and catalase activity, blood haemoglobin content and catalase activity and brain respiratory cytochromes were measured. These tissues give a measure of haemoproteins in the two major haem containing organs, the liver and blood and a measure of haemoproteins in neural tissue where a deficit, in these cytochromes, could lead to neuropathy. 9. Treatments which included the use of either 4-ethyl DDC or N-methyl protoporphyrin, both of which inhibit hepatic ferrochelatase, caused a significant reduction in hepatic haemoproteins, but were ineffective in reducing blood or brain levels. Lead treatment did cause a reduction in whole blood haemoglobin content and a rise in catalase activity, but was also incapable of reducing brain respiratory cytochrome levels. 10. The failure of these porphyrinogenic compounds to alter brain haemoproteins may be due to their inability to cross the blood brain barrier. 11. The last group of experiments examined both hepatic and brain mitochondrial function following porphyrinogenic treatment, which was known, from the previous group of experiments, to reduce hepatic respiratory cytochromes. Additionlly, to circumvent the blood brain barrier, the ferrochelatase inhibitor, N-methyl protoporphyrin was administered directly into the ventricular system. Treatments which significantly reduced hepatic respiratory cytochromes also caused a reduction in the Respiratory Control Ratio (RCR) in liver mitochondria, while all other respiratory parameters were unaltered. All brain mitochondrial function parameters were unaltered by these systemic treatments. Central administration of N-methyl protoporphyrin, caused a reduction in brain mitochondrial RCRs, while all other respiratory parameters in this tissue remained unaltered. Hepatic mitochondrial function was unaffected by centrally-administered N-methyl protoporphyrin. 12. The results of these experiments show that some porphyrinogenic drugs are capable of altering some aspects of mitochondrial function, in this case the Respiratory Control Ratio (RCR). Although systemically-administered compounds were unable to alter brain mitochondrial function, while doing so in liver, N-methyl protoporphyin did reduce RCR's in brain mitochondria when administered centrally. This latter observation suggests that when porphyrinogenic drugs gain access to neural tissue they can exert similar effects. 13. The failure, in this study, to produce a neuropharmacological model of acute porphyria is most probably due to the inability of the porphyrinogenic compounds employed to reduce neural respiratory cytochromes to levels where a functional deficit occurs. This problem may be overcome by a longer period of treatment. The results of the present set of experiments indicate that succinylacetone is not a suitable compound for use in in vivo haemoprotein depletion. N-methyl protoporphyrin at larger concentrations than used in this study may be more effective in producing a model of a haem deficiency neuropathy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796779  DOI: Not available
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