Biomedical subjects
Publications and source records attributed to J R Rapin.
This paper studies three possible sites of action of drugs used for treatment of symptoms in ageing: blood (increasing flow, capillary bed, nutriment supply), the blood brain barrier (stabilization and/or increase of transfer rate), and the cell (increasing energetics, intermediary and/or neurotransmitter metabolism).
Memory loss and similar cognitive associated dysfunctions are commonly recognized as being the most serious symptoms of ageing and dementia. In this work, a deterioration of cognitive function which is appreciated in old rats (learning test in a maze--or, in aged humans, memory verbal test) is determined during the measurement of local cerebral blood flow and metabolism. In the animal, the disturbance by the learning test is observed by a decrease of blood flow in the hippocampus, diencephalon, and corpus striatum. In man, the cognitive dysfunctions appear although there is an increase of blood flow in the frontal cortex. These data show a new organization in the ageing brain which only appears during cerebral stimulation.
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Cytotoxic effects of Bleomycin A2 on adult rat liver epithelial cell lines were evaluated by three methods: the incorporation rate of (3H) thymidine for DNA biosynthesis, the incorporation rate of L-(3H) leucine for protein biosynthesis and Giemsa dye staining of surviving cells. Chromosome investigations at successive passages of cell lines have shown that spontaneous chromosome abnormalities in distribution and structure after 15-20 passages, i.e. 50 to 60 cell generations, were the earliest morphological sign of spontaneous transformation. In this study a highly spontaneously transformed cell line was very sensitive to the drug. Another cell line at the beginning of spontaneous transformation appeared to be insensitive although on further passage it became more sensitive. The use of microtitration plates made it easier for us to undertake a comparative study of the different parameters. Following Bleomycin A2 exposure, Giemsa staining gave the best evaluation of cell killing whereas thymidine incorporation allowed the estimation of cell recovery. The antineoplastic effect of Bleomycin A2 can probably be used to evaluate the malignant potential of different rat liver epithelial cell lines.
In anesthetized adult cats, acute stroke was produced by transorbital occlusion of the left middle cerebral artery. A battery of imaging techniques was used for simultaneous evaluation of regional blood flow, glucose utilization, protein synthesis, pH, and the regional tissue content of glucose, ATP, and potassium. The electrophysiological impact of stroke was monitored by EEG frequency analysis and recording of somatosensory evoked potentials. Two hours after vascular occlusion, a close correlation existed between the degree of electrophysiological changes and biochemical alterations, in particular with the extent of tissue acidosis, ATP depletion, decrease of tissue potassium content, and suppression of protein synthesis. However, there was only a poor correlation with blood flow and glucose utilization. Both of these exhibited a greatly inhomogeneous pattern with regions of reduced, normal, or increased rates. In areas remote from the infarct, the content of biochemical substrates was normal but blood flow was reduced globally by approximately 50% and glucose utilization by approximately 20%. An anatomically defined regional pattern of cerebral or cerebellar diaschisis was not observed. It is concluded that during the acute phase of stroke, imaging of blood flow and glucose utilization does not provide an accurate estimate of the actual functional or metabolic disturbance. For the clinical evaluation of the development or treatment of stroke, in consequence, alternative noninvasive techniques such as imaging of protein synthesis and/or pH may be more relevant.
In the present work, a study of the number of functional receptors has been made with 3HQNB given to resting awaken animals during a learning process. Ageing leads to a decrease in the ability of learning associated with an increase in the number of large movements. The number of cholinergic receptors is also reducel if we compare 22 month old animals with 4 month old animals maintained under usual conditions. Learning conditioning leads to a stimulation of the cholinergic system with a release of acetylcholine. The mediator takes the 3HQNB out of its fixation areas which causes an apparent decrease in the number of receptors. This result is more significant in young animals than in aged ones because of the possibility of activation in the cholinergic system. The treatment by dihydroergotoxine partially re-establishes the learning abilities in animals and, at the same time, increases the number of cholinergic receptors This effect could explain the actions of this drug on the memory process in ageing persons.
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Rats were injected with iodoamphetamine synthesized and labeled with 125I or with 125I- isopropyliodoamphetamine , a molecule of established value for the determination of local cerebral blood flow. The blood kinetics, tissue distribution, and brain uptake index for each tracer exhibited practically no differences. Autoradiographic quantification of the local cerebral blood flow, calculated according to the microsphere model, produced identical results for both molecules. However, compared with the values reported for other tracers, our values constituted an underestimation of white matter blood flow and a more real estimation of hippocampal flow. It is concluded from the brain uptake of the derivatives of both amphetamines during the first minutes following their injection that these tracers can be used as a chemical microembolus for the measurement of local cerebral blood flow.
The influence of aging and the effects of treatment with dihydrogenated rye ergot alkaloid on cerebral hemodynamics and metabolism were studied in Long-Evans rats. Cerebral blood flow (CBF) was not affected by aging whereas the vascular bed and the uptake of deoxyglucose were significantly lower in aged than in young rats. 20 days after ligation of a carotid artery the blood flow on the same side of the brain, the vascular bed and the uptake of deoxyglucose were significantly lowered in aged rats as opposed to young rats. The second carotid artery was ligated 1 h before the animals were sacrificed: in the corresponding cerebral hemisphere the blood flow was found to be significantly lowered in young rats and even more so in aged rats. These results show that young rats are more likely to adapt to an acute or chronic circulatory deficiency than aged rats. Dihydroergocryptine ( DHEC , 0.1 mg/kg/day for 5 days, p.o.) reduces CBF and the vascular bed in aged rats, as opposed to dihydroergotoxine ( DHET , 5 X 0.1 mg/kg/day p.o.). The uptake of deoxyglucose was not influenced by the treatments. After ligation of the carotid arteries, treatment with DHEC and DHET induced an increase in CBF without any change in the vascular bed and, in the case of DHEC only, there was a significant increase in the uptake of deoxyglucose in the cerebral hemisphere submitted to acute circulatory deficiency. DHEC and DHET thus exerted significant effects on cerebral metabolism and hemodynamics in the aged rats after repeated oral treatment.
Unilateral cerebral ischaemia was induced in 18-month-old Long-Evans rats by injection of 2,000 labelled microspheres (phi 50 microns) into the carotid blood stream. This results in an ipsilateral decrease in cerebral blood flow, development of severe oedema and modifications of glucose uptake and consumption. Furthermore, this ischaemia led to a deterioration of the avoidance response in conditioned animals. All these disturbances, including the cerebral oedema, diminished with nicergoline pretreatment.
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The effects of ageing in normal and pathological rats were studied. Learning (spatio-temporal test) was measured simultaneously with the local cerebral blood flow, determined by a diffusible indicator (iodoantipyrine) and with the uptake and consumption of glucose, determined by the deoxyglucose. Normal ageing disturbs the learning with a decrease in acquisition speed and an increase in the number of errors. Furthermore, normal ageing induces a decrease in glucose uptake and in glucose consumption in the brain structures such as hippocampus or corpus striatum, with only a slight decrease in local cerebral blood flow. Dihydroergotoxine partially reestablishes the performances of the rats and increases the glucose consumption in the areas involved in learning. Pathological ageing, produced by the administration of microspheres and corresponding to the multi-infarct dementia, is correlated to a large decrease in glucose consumption and local blood flow. Dihydroergotoxine treatment partially suppresses the micro-infarct effects before the reestablishment of rat performance in behavioral tests.
Among the iodophenylalkylamines studied and labelled with iodine 125 or iodine 123, N-isopropyl-iodo-amphetamin (IAMP) was selected and proposed as tracer for blood flow, a "chemical embolus" having almost 100% extraction in the brain. A new way of obtaining N-isopropyl-p-iodo-amphetamin is proposed and the easily-applied exchange reaction with iodine 125 or 123 gives a product with a radiochemical purity of more than 96% and an unexchanged radioactive iodine content of less than 1%. The pharmacokinetic study of this product in the Wistar rat showed distribution in three compartments and the appearance of a steady state by the fourth minute. The target organs are the lungs, liver and brain. The latter receives 3% of the radioactivity and the autoradiographic study shows that the early distribution in the brain for IAMP closely equals the blood flow as found by a diffusible indicator. In the first hour, the redistribution is very low and at this time although IAMP is proposed for the study of regional blood flow, it does not exactly determine the flow but rather mirrors cell activity.
In Long Evans rats, the vertebral arteries supply only the brain stem. Simultaneous application of clamps to both carotid arteries results in a considerable fall of cerebral blood flow and eventually death. If an interval of about 4 days is allowed between the clamping of the 2 carotids, redistribution of blood flow takes place. Owing to this mechanism, 50% of the rats survive with a satisfactory restoration of cerebral blood flow.
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