Biomedical subjects

J E Brecknell

Publications and source records attributed to J E Brecknell.

5 recordsLinked to original sources

PubMed1996

A device for the implantation of multiple cellular deposits into a large volume of brain from a single cannula site.

Current grafting techniques for the treatment of Parkinson's disease incompletely restore the dopaminergic innervation of the caudate/putamen and while, in successful cases, bradykinesia and rigidity are reduced, tremor is largely unaffected. Increasing the number of cellular deposits would allow grafted neurons to be dispersed more widely within the host brain. This might be expected to lead to a more complete reinnervation of the caudate/putamen and therefore a better clinical result. In order to increase the volume of brain accessible to reinnervation without increasing the number of needle passages through the cortex, we have designed a device which allows a Teflon tube to be extruded sideways from the end of a stainless steel cannula. Through this tube, cells can be implanted at some distance in any radial direction from the axis of the cannula. Using such a device we have made up to 12 deposits of lac-z-labeled cells via a single cannula entry into the rat brain, at distances of up to 5 mm from the axis of the cannula. We propose that a similar device could be used to graft embryonic neurons into the human brain.

Animals↗

PubMed1996

Functional and anatomical reconstruction of the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat.

In an attempt to reconstruct the 6-hydroxydopamine lesioned nigrostriatal system of the adult rat we have combined homotopic grafting of embryonic ventral mesencephalon suspensions with the implantation of long oblique "bridge" grafts of fibroblast growth factor-4-transfected RN-22 schwannoma cells stretching from the site of the neuronal grafts to the striatum. At seven weeks after receiving both grafts, animals were killed and processed for immunohistochemistry against tyrosine hydroxylase. Tyrosine hydroxylase-immunoreactive axons were seen to extend from the nigral grafts, along the bridge graft to the striatum where terminal arborizations could be seen. The retrograde tracer Fluoro-gold was injected intrastriatally in some of the experimental animals and was taken up by grafted neurons confirming their projection to the striatum. In parallel to the anatomical reconstruction of the system, a decrease in amphetamine-induced rotation was demonstrated in those animals receiving both grafts which had received > 98% complete lesions. This decrease was greatest in those animals with the most tyrosine hydroxylase-immunoreactive axons in their bridge grafts. The presence of the bridge graft also led to an increase in neuronal graft survival with twice as many tyrosine hydroxylase-immunoreactive neurons being found in the grafts of those animals that had received both grafts compared to those that had received a neuronal graft but no bridge graft.

Amphetamine↗

PubMed1996

Bridge grafts of fibroblast growth factor-4-secreting schwannoma cells promote functional axonal regeneration in the nigrostriatal pathway of the adult rat.

Axons damaged in the adult mammalian central nervous system are able to regenerate when their inhibitory glial environment is replaced with a more permissive substrate. Here, we have used long oblique "bridge" grafts of fibroblast growth factor-4-transfected RN-22 schwannoma cells to allow mechanically lesioned nigrostriatal axons to regenerate back to their original target in the adult rat brain. Regenerated axons were able to leave the bridge graft to form terminal arborizations and increase the density of tyrosine hydroxylase-immunoreactive fibres within the striatum. Bridge grafting also resulted in an increase in the number of neurons within the substantia nigra pars compacta taking up the fluorescent retrograde tracer Fluoro-Gold from the striatum. Animals which had received RN-22 bridge grafts showed lower rates of amphetamine-induced rotation 10 weeks after a mechanical lesion of the nigrostriatal tract compared to lesioned controls, the magnitude of the behavioural effect being related to the number of regenerated axons, and this comparative reduction was reversed by mechanical section of the bridge graft. It is concluded that our bridge grafting strategy allowed the partial anatomical and functional regeneration of the mechanically lesioned nigrostriatal tract, an unmyelinated central axon bundle, and that bridge grafting therefore represents a realistic approach to the repair of central nervous system lesions involving axon tract damage.

Amphetamine↗

PubMed1996

Axonal regeneration.

Axons damaged in a peripheral nerve are often able to regenerate from the site of injury along the degenerate distal segment of the nerve to reform functional synapses. Schwann cells play a central role in this process. However, in the adult mammalian central nervous system, from which Schwann cells are absent, axonal regeneration does not progress to allow functional recovery. This is due to inhibitors of axonal growth produced by both oligodendrocytes and astrocytes and also to the decreased ability of adult neurons to extend axons during regeneration compared to embryonic neurons during development. However once provided with a substrate conducive to axonal growth, such as a peripheral nerve graft, many central neurons are able to regenerate axons over long distances. Over the past year this response has been utilised in experimental models to produce a degree of behavioural recovery.

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PubMed1995

A quantitative study of cell death in the substantia nigra following a mechanical lesion of the medial forebrain bundle.

An extruding wire knife was used to give adult male CFHB rats a minimally traumatic unilateral mechanical lesion of the medial forebrain bundle. In addition, some rats received bilateral intrastriatal injections of one of three fluorescent retrograde tracers either eight days before or eight days after the lesion. Injections made after the lesion revealed that about half of the animals had complete lesions of the nigrostriatal tract, while the other half were incompletely lesioned, the mean proportion of non-axotomized neurons being 23%. Over the 10 weeks following the lesions, the number of tyrosine hydroxylase-immunoreactive cells in the lesioned substantia nigra fell linearly, reaching a mean of 29% of that of the control substantia nigra. In the animals which were completely lesioned, neuronal survival at 10 weeks varied between 6 and 12%. That the disappearance of tyrosine hydroxylase-immunoreactive neurons was due to cell death rather than the loss of tyrosine hydroxylase itself was confirmed by labelling the cells with Fluoro Gold before axotomy; the tracer was seen in survival neurons, microglia and in a few involuted neurons which continued to be tyrosine hydroxylase-immunoreactive. This percentage of neurons surviving axotomy corresponds to the proportion of substantia nigra neurons which project to the contralateral striatum, and these neurons were in the region of the substantia nigra from which the contralateral projection originated. It is concluded that following mechanical transection of the nigrostriatal tract, all truly axotomized substantia nigra neurons die over a period of about 10 weeks.

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