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Brain implants in man do not break down the blood-brain barrier to dopamine and domperidone
Brain Research, 536 (199t)) 31t';-32~i ElsevieT
318
BRES 24433
Brain implants in man do not break down the blood-brain barrier to dopamine and domperidone C.G. Clough, E.R. Hitchcock, R.C. Hughes, B.T. Henderson and B.G. Kenny Department of Neurosurgery, University of Birmingham, Midland Centre for Neurosurgery and Neurology, Smethwick, Warley, West Midlands (U. K.)
(Accepted 4 September 1990) Key words: Parkinson's disease; Blood-brain barrier; Neural transplantation
We have evaluated the blood-brain barrier (BBB) in 8 Parkinsonian patients before and after stereotactic implantation of foetal mesencephalon (STIM) and one patient with an adrenal medullary implant. Parenteral administration of dopamine did not reverse Parkinsonism pre-operatively or at 5 days 1, 2, 3, 4 months and one year post-operatively. Apomorphine and domperidone reversed Parkinsonism and produced dyskinesia in all patients pre- and post-operatively. We conclude that the BBB remains intact to dopamine following implantation. Early improvement in Parkinson's disease following operation has been observed by several investigators following implantation of autologous adrenal medulla 1"9 or foetal mesencephalon 8'1° into the caudate nucleus. In non-human primate PD models improvement occurred after 18 days a4 although in rodents the effects of implants take several weeks or months to emerge. Dopamine neuronal transplants in animals survive, secrete dopamine and form neural connections 2'13"14 which may explain the behavioural changes after implantation but not the early improvement in non-human primates and man. An alternative explanation is that the surgical lesion improves Parkinsonism 16 although there is contrary evidence 12. Implants could disorder the BBB H or create a 'channel' permitting endogenous or exogenous catecholamines to stimulate dopamine receptors. Neocortical implants lack a blood-brain barrier to macromolecules 15. Reversal of Parkinsonism or a dyskinetic 'on' state can occur within minutes of caudate implantation implying increased dopaminergic activity8. Dopamine does not cross the blood-brain barrier so cannot reverse Parkinsonism but intra-ventricular dopamine reverses reserpine-induced akinesia in rats 6 and causes spontaneous contralateral rotation in 6-OHDA-lesioned rats as does apomorphine presumably by activation of dopamine receptors 5. A significant surgical breach in the BBB could permit access of intravenous dopamine into the striatum and reverse Parkinsonism. Apomorphine reverses Parkinsonism within minutes of
subcutaneous administration 4 and theoretically could be used to assess dopamine receptor availability. A peripherally acting dopamine blocker domperidone can be combined with apomorphine to prevent nausea. The central action of apomorphine could be blocked by access of domperidone to striatal receptors through a deficient BBB. A series of patients with severe PD and a positive response to L-dopa were treated by foetal mesencephalic caudate implantation 7. The post-op clinical ratings are shown in Fig. 1. An additional patient ( L D . ) was treated with autologous adrenal implant. All were taking levodopa preparations, 3 were taking anticholinergics. The exception was J.D. whose drug therapy was discontinued pre-operatively. The test was performed at the same time of day, 6 h after the last dose of Levodopa. All patients gave informed consent. Each of the 4 limbs were rated separately for bradykinesia, rigidity and tremor on the Webster Rating Scale (WRS). Twelve parameters were scored from 0 to 3, the maximum score possible being 36. Ratings were performed by two experienced observers; temporal fluctuations during the test but prior to drug administration did not exceed 5% and required no rating adjustment. Intravenous dopamine was given over 30 min at a dose of 50/~g/min increasing gradually to a maximum of 2000 pg/min, until side-effects supervened or the blood pressure rose beyond safe limits; all patients had at least 1600 ag/min. At the end of the dopamine infusion 20 mg domperidone was given orally followed 20 min later by
Correspondence: E.R. Hitchcock, Department of Neurosurgery, Midland Centre for Neurosurgery and Neurology, Holly Lane, Smethwick, Warley, West Midlands B67 7JX, U.K.
0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
319 TABLE I Percent improvement in Parkinsonian score with dopamine (DA) and apomorphine (Apom) after right caudate implantation Patient
Sex
Age
Pre-op
Post-op
DA
Apom
87 60 33 59
DA
Apom
Group A
K.G. R.L. C.B.
M M M
54 67 60
0 -5 0
B.S.
M
53
0
M F F M M
57 58 60 41 46
0 -7 0 12
80 80 42 46
0 -10.5 0 -9 0
62 30 62 58 50
Group B
C.T. R.S. E.K. R.D. J.D.*
* Autologous adrenal implant.
1.5 mg apomorphine s.c. Parkinsonian scores were then recorded immediately and every 5 min until improvement and dyskinesia was noted. Four patients (Group A) were tested the week prior to implantation and again 5 days post-implantation. Five patients (Group B) were tested once only at 1, 2, 3, 4 months and 1 year post-operatively, respectively. The effect of parenteral dopamine on peripheral dopaminergic receptors was demonstrated by an initial fall in BP in 5 of 9 patients (average 23 mm systolic and 16 mm diastolic) while 7 of 9 had elevated BP with higher dopamine doses (average 30 mm systolic and 9 mm diastolic). Dopamine infusion did not significantly change the Parkinsonian score either pre- or postimplant; apomorphine with domperidone was invariably associated with a marked bilateral improvement in Parkinsonian scores (Table I). The onset of improvement and dyskinesia was recorded as a positive response and was unaltered at 1, 2, 3, 4 months post-implant. The response to apomorphine was invariable and dramatic
occurring within seconds and usually heralded by yawning. Peak response was complete within 1-2 min reaching a plateau lasting for at least 30 rain. The time of onset of this 'on period' was 14 min (range = 8-20 min) pre-operatively and 11.5 min (range = 7-17 min) post-operatively. Pre- and post-operatively the apomorphine response was not significantly different nor was there significant change in Parkinsonian scores (Table I). In J.D. the adrenal implant, although buried in the caudate head, remains exposed to the CSF, but he had the same test response one year later. The close similarity of pre- and post-implant responses to both dopamine infusions and apomorphine/domperidone seems to establish the pharmacological integrity of the blood-brain barrier (BBB) in these patients. If there had been a significant breakdown in BBB at the site of the implant, or a 'channel' created in these patients, dopamine would have had access to striatal dopamine receptors and hence reversal of Parkinsonism and the onset of dyskinesia should have occurred. The high dose of dopamine used and the long infusion time (30 min) was adequate and sufficient to produce a response. Intraventricular infusion of dopamine in rats rendered Parkinsonian by reserpine does not reverse rigidity unless monoamine oxidase inhibitors are given 6. However, the same workers found that intraventricular dopamine caused spontaneous contralateral rotation in the 6-OHDAlesioned rat without monoamine oxidase inhibitors 5. This is a model similar to our own test situation since we have subsequently blocked monoamine oxidase activity using selegiline (10 mg) and repeated the dopamine test although only in 2 patients, without producing improvement. The emphatic positive response to apomorphine demonstrates that dopamine receptors are still available for stimulation. The similar and bilateral nature of the response before and after operation reassures us that no significant damage to post-synaptic striatal dopamine
PERCENTAGE CHANGEWRS "ON"SCORES
PERCENTAGECHANGEWRS "OFFSCORES rl.8
~-
4 5 S 7
4,11-
Time
(months)
Time
Fig. 1. Changes in WRS and NUDS 'on' and 'off' in 8 patients during the 6 months post-operative period.
(months)
318
BRES 24433
Brain implants in man do not break down the blood-brain barrier to dopamine and domperidone C.G. Clough, E.R. Hitchcock, R.C. Hughes, B.T. Henderson and B.G. Kenny Department of Neurosurgery, University of Birmingham, Midland Centre for Neurosurgery and Neurology, Smethwick, Warley, West Midlands (U. K.)
(Accepted 4 September 1990) Key words: Parkinson's disease; Blood-brain barrier; Neural transplantation
We have evaluated the blood-brain barrier (BBB) in 8 Parkinsonian patients before and after stereotactic implantation of foetal mesencephalon (STIM) and one patient with an adrenal medullary implant. Parenteral administration of dopamine did not reverse Parkinsonism pre-operatively or at 5 days 1, 2, 3, 4 months and one year post-operatively. Apomorphine and domperidone reversed Parkinsonism and produced dyskinesia in all patients pre- and post-operatively. We conclude that the BBB remains intact to dopamine following implantation. Early improvement in Parkinson's disease following operation has been observed by several investigators following implantation of autologous adrenal medulla 1"9 or foetal mesencephalon 8'1° into the caudate nucleus. In non-human primate PD models improvement occurred after 18 days a4 although in rodents the effects of implants take several weeks or months to emerge. Dopamine neuronal transplants in animals survive, secrete dopamine and form neural connections 2'13"14 which may explain the behavioural changes after implantation but not the early improvement in non-human primates and man. An alternative explanation is that the surgical lesion improves Parkinsonism 16 although there is contrary evidence 12. Implants could disorder the BBB H or create a 'channel' permitting endogenous or exogenous catecholamines to stimulate dopamine receptors. Neocortical implants lack a blood-brain barrier to macromolecules 15. Reversal of Parkinsonism or a dyskinetic 'on' state can occur within minutes of caudate implantation implying increased dopaminergic activity8. Dopamine does not cross the blood-brain barrier so cannot reverse Parkinsonism but intra-ventricular dopamine reverses reserpine-induced akinesia in rats 6 and causes spontaneous contralateral rotation in 6-OHDA-lesioned rats as does apomorphine presumably by activation of dopamine receptors 5. A significant surgical breach in the BBB could permit access of intravenous dopamine into the striatum and reverse Parkinsonism. Apomorphine reverses Parkinsonism within minutes of
subcutaneous administration 4 and theoretically could be used to assess dopamine receptor availability. A peripherally acting dopamine blocker domperidone can be combined with apomorphine to prevent nausea. The central action of apomorphine could be blocked by access of domperidone to striatal receptors through a deficient BBB. A series of patients with severe PD and a positive response to L-dopa were treated by foetal mesencephalic caudate implantation 7. The post-op clinical ratings are shown in Fig. 1. An additional patient ( L D . ) was treated with autologous adrenal implant. All were taking levodopa preparations, 3 were taking anticholinergics. The exception was J.D. whose drug therapy was discontinued pre-operatively. The test was performed at the same time of day, 6 h after the last dose of Levodopa. All patients gave informed consent. Each of the 4 limbs were rated separately for bradykinesia, rigidity and tremor on the Webster Rating Scale (WRS). Twelve parameters were scored from 0 to 3, the maximum score possible being 36. Ratings were performed by two experienced observers; temporal fluctuations during the test but prior to drug administration did not exceed 5% and required no rating adjustment. Intravenous dopamine was given over 30 min at a dose of 50/~g/min increasing gradually to a maximum of 2000 pg/min, until side-effects supervened or the blood pressure rose beyond safe limits; all patients had at least 1600 ag/min. At the end of the dopamine infusion 20 mg domperidone was given orally followed 20 min later by
Correspondence: E.R. Hitchcock, Department of Neurosurgery, Midland Centre for Neurosurgery and Neurology, Holly Lane, Smethwick, Warley, West Midlands B67 7JX, U.K.
0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
319 TABLE I Percent improvement in Parkinsonian score with dopamine (DA) and apomorphine (Apom) after right caudate implantation Patient
Sex
Age
Pre-op
Post-op
DA
Apom
87 60 33 59
DA
Apom
Group A
K.G. R.L. C.B.
M M M
54 67 60
0 -5 0
B.S.
M
53
0
M F F M M
57 58 60 41 46
0 -7 0 12
80 80 42 46
0 -10.5 0 -9 0
62 30 62 58 50
Group B
C.T. R.S. E.K. R.D. J.D.*
* Autologous adrenal implant.
1.5 mg apomorphine s.c. Parkinsonian scores were then recorded immediately and every 5 min until improvement and dyskinesia was noted. Four patients (Group A) were tested the week prior to implantation and again 5 days post-implantation. Five patients (Group B) were tested once only at 1, 2, 3, 4 months and 1 year post-operatively, respectively. The effect of parenteral dopamine on peripheral dopaminergic receptors was demonstrated by an initial fall in BP in 5 of 9 patients (average 23 mm systolic and 16 mm diastolic) while 7 of 9 had elevated BP with higher dopamine doses (average 30 mm systolic and 9 mm diastolic). Dopamine infusion did not significantly change the Parkinsonian score either pre- or postimplant; apomorphine with domperidone was invariably associated with a marked bilateral improvement in Parkinsonian scores (Table I). The onset of improvement and dyskinesia was recorded as a positive response and was unaltered at 1, 2, 3, 4 months post-implant. The response to apomorphine was invariable and dramatic
occurring within seconds and usually heralded by yawning. Peak response was complete within 1-2 min reaching a plateau lasting for at least 30 rain. The time of onset of this 'on period' was 14 min (range = 8-20 min) pre-operatively and 11.5 min (range = 7-17 min) post-operatively. Pre- and post-operatively the apomorphine response was not significantly different nor was there significant change in Parkinsonian scores (Table I). In J.D. the adrenal implant, although buried in the caudate head, remains exposed to the CSF, but he had the same test response one year later. The close similarity of pre- and post-implant responses to both dopamine infusions and apomorphine/domperidone seems to establish the pharmacological integrity of the blood-brain barrier (BBB) in these patients. If there had been a significant breakdown in BBB at the site of the implant, or a 'channel' created in these patients, dopamine would have had access to striatal dopamine receptors and hence reversal of Parkinsonism and the onset of dyskinesia should have occurred. The high dose of dopamine used and the long infusion time (30 min) was adequate and sufficient to produce a response. Intraventricular infusion of dopamine in rats rendered Parkinsonian by reserpine does not reverse rigidity unless monoamine oxidase inhibitors are given 6. However, the same workers found that intraventricular dopamine caused spontaneous contralateral rotation in the 6-OHDAlesioned rat without monoamine oxidase inhibitors 5. This is a model similar to our own test situation since we have subsequently blocked monoamine oxidase activity using selegiline (10 mg) and repeated the dopamine test although only in 2 patients, without producing improvement. The emphatic positive response to apomorphine demonstrates that dopamine receptors are still available for stimulation. The similar and bilateral nature of the response before and after operation reassures us that no significant damage to post-synaptic striatal dopamine
PERCENTAGE CHANGEWRS "ON"SCORES
PERCENTAGECHANGEWRS "OFFSCORES rl.8
~-
4 5 S 7
4,11-
Time
(months)
Time
Fig. 1. Changes in WRS and NUDS 'on' and 'off' in 8 patients during the 6 months post-operative period.
(months)