(Stroke. 1999;30:696-698.)
© 1999 American Heart Association, Inc.
Letters to the Editor |
Amphetamine-Facilitated Poststroke Recovery
Department of Medicine (Neurology), Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University, and Durham VA Medical Center, Durham, North Carolina
To the Editor:
The poststroke recovery period represents a largely unexplored potential "window of opportunity" for therapeutic intervention. The studies by Stroemer and colleagues1 represent a significant contribution to our evolving understanding of the neurobiological processes underlying poststroke behavioral recovery and the potential mechanisms by which that recovery may be facilitated by treatment with amphetamine. These findings are of particular interest in view of other laboratory and clinically based reports.
Several lines of evidence suggest that amphetamine's effect on
recovery is at least in part noradrenergically
mediated. Pharmacological experiments have shown that centrally-acting
2-adrenergic receptor antagonists
increase the rate of motor recovery,2 3 4 5 whereas the
administration of an 2-adrenergic receptor
agonist3 6 or selective
1-adrenergic receptor antagonists
are detrimental.3 4 Furthermore, as referenced by Stroemer
and colleagues,1 we found that pretreatment with a
neurotoxin that depletes central norepinephrine
(N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine)
impairs motor recovery,7 a finding subsequently
confirmed by others.8 Consistent with this result,
intraventricular infusion of
norepinephrine mimics the effect of
amphetamine.9
The results of these pharmacological studies are supported by experiments in which selective lesions were placed in the pontine nucleus locus coeruleus (LC), the major source of central noradrenergic projection fibers.10 11 In rats, bilateral LC lesions 2 weeks prior to a right sensorimotor cortex lesion resulted in poorer behavioral recoveries when compared with rats that had sham LC lesions.12 13 Unilateral LC lesions, either ipsilateral or contralateral to a sensorimotor cortex lesion, also affect recovery, although the results obtained by individual laboratories vary.12 13
Because LC neurons are highly collateralized,14 15 16 LC lesioning experiments cannot be used to determine whether noradrenergic regulation of motor recovery after unilateral sensorimotor cortex injury is exerted at the level of the ipsilateral or contralateral cerebral cortex, the ipsilateral or contralateral cerebellum, or other brain structures. We recently reported that a prior selective lesion of noradrenergic projection fibers (dorsal noradrenergic bundle) to the cerebral cortex contralateral, but not ipsilateral, to a subsequent sensorimotor cortex lesion impairs the recovery of locomotor ability.17 This finding is intriguing in view of the earlier18 and present1 observations of Stroemer and colleagues of a significant increase of synaptophysin immunoreactivity in the contralateral parietal cortex of amphetamine treated rats. Interestingly, positron emission tomography studies of humans who had recovered motor function after hemiplegic stroke have shown significant increases in regional cerebral blood flow induced by movement of the recovered limb in the sensorimotor cortex contralateral to the injury.19 Similar changes in the contralateral hemisphere of patients recovering motor function after stroke have now also been demonstrated with functional MRI.20 21 22 Considered together, these findings suggest that amphetamine may exert its impact on recovery through effects on processes in the contralateral hemisphere. These contralateral effects could also secondarily influence onging neuronal reorganization in the hemisphere ipsilateral to the injury.
A pilot clinical study of amphetamine-promoted poststroke motor recovery in humans found that the effect varied among individual patients.23 Some patients had a dramatic improvement of motor ability, whereas the benefit was only marginal in others. Combining advances in our knowledge of the mechanism of amphetamine- (and noradrenergically) mediated recovery with information obtainable with new neuroimaging technologies may allow the selection of patients who may benefit from these types of interventions in the future.
References
1.
Stroemer RP, Kent TA, Hulsebosch CE.
Enhanced neocortical neural sprouting, synaptogenesis, and behavioral
recovery with D-amphetamine therapy after neocortical infarction in
rats. Stroke. 1998;29:2381–2395.
2. Goldstein LB. Amphetamine-facilitated functional recovery after stroke. In: Ginsberg MD, Dietrich WD, eds. Cerebrovascular Diseases: Sixteenth Research (Princeton) Conference. New York, NY: Raven Press; 1989:303–308.
3. Feeney DM, Westerberg VS. Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol. 1990;44:233–252.[Medline] [Order article via Infotrieve]
4.
Sutton RL, Feeney DM.
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5.
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Ann Neurol. 1989;26:157. Abstract.
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8. Boyeson MG, Callister TR, Cavazos JE. Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4. Behav Neurosci. 1992;106:964–973.[Medline] [Order article via Infotrieve]
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13. Goldstein LB. Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat. Restor Neurol Neurosci. 1997;11:55–63.
14. Room P, Postema F, Korf J. Divergent axon collaterals of rat locus coeruleus neurons: demonstration by a fluorescent double labeling technique. Brain Res. 1981;221:219–230.[Medline] [Order article via Infotrieve]
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16. Kobayashi RM, Palkovitz M, Kopin IJ, Jacobowitz DM. Biochemical mapping of noradrenergic nerves arising from the rat locus coeruleus. Brain Res. 1974;77:269–279.[Medline] [Order article via Infotrieve]
17. Goldstein LB, Bullman S. Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury. Pharmacol Biochem Behav. 1997;58:1151–1157.[Medline] [Order article via Infotrieve]
18.
Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural
sprouting, synaptogenesis, and behavioral recovery after neocortical
infarction in rats. Stroke. 1995;26:2135–2144.
19. Chollet F, DiPiero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol. 1991;29:63–71.[Medline] [Order article via Infotrieve]
20.
Cao Y, D'Olhaberriague L, Vikingstad EM, Levine SR,
Welch KMA. Pilot study of functional MRI to assess cerebral activation
of motor function after poststroke hemiparesis. Stroke. 1998;29:112–122.
21.
Cramer SC, Nelles G, Benson RR, Kaplan JD, Parker RA,
Kwong KK, Kennedy DN, Finklestein SP, Rosen BR. A functional MRI study
of subjects recovered from hemiparetic stroke. Stroke. 1997;28:2518–2527.
22.
Silvestrini M, Cupini LM, Placidi F, Diomedi M,
Bernardi G. Bilateral hemispheric activation in the early recovery of
motor function after stroke. Stroke. 1998;29:1305–1310.
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Response
Department of Anatomy and Neurosciences, Marine Biomedical Institute, University of Texas Medical Branch, Galveston, Texas
Key Words: amphetamines • cerebral
ischemia • neuronal plasticity
The poststroke recovery period has traditionally consisted of symptom management and physical therapy.1 2 3 Few therapeutic agents have proved successful in improving patient outcome. For example, several pharmacological agents (eg, calcium channel antagonists, excitatory amino acid antagonist) have the potential to reduce ischemic damage3 4 5 but have problematic side effects and must be applied within minutes of the injury. Thus, not only the treatment strategy but the therapeutic window of efficacy must be considered and must be in a clinically useful window for patient treatment. Most stroke patients do not seek medical help within 6 hours after the onset of clinical symptoms,6 and thus it is important to pursue therapeutic interventions that are efficacious when administered 24 hours or more after ischemia.
Over the past few years, several pivotal studies have supported the promising use of D-amphetamine treatment in poststroke patients because of both the improved functional recovery7 and the prolonged therapeutic window of opportunity (several days) available for drug efficacy.8 9 10 Recent work by our group addresses several possible mechanisms of recovery11 and improved recovery after D-amphetamine treatment in a rodent neocortical ischemia model.12 We suggest that multiple mechanisms underlie this treatment, including the amelioration of metabolic depression. Our work proposes a novel mechanism, neuritogenesis and synaptogenesis, as one of several important components in the pathophysiology of improved behavioral response after ischemia and D-amphetamine treatment.12 Another mechanism of recovery involves D-amphetamine enhancement of noradrenergic-mediated mechanisms, several of which are discussed in the article by Stroemer et al12 and its accompanying editorial comment by Dennis Feeney.13 The letter to the editor by Larry Goldstein does an excellent job of further expanding and extending the understanding of the mechanistic basis of D-amphetamine–stimulated, noradrenergically mediated recovery of function after ischemia by discussing several articles that we were unable to include in the original work by our group because of space limitations. We wish to thank Dr Goldstein for his comments regarding the "significant contribution" of our previous manuscript and for the additional discussion, which we recommend be read in tandem with our article.12
References
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2.
Twitchell TE. The restoration of motor function
following hemiplegia in man. Brain. 1951;74:443–480.
3. Choi DW. Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci. 1990;10:2493–2501.[Medline] [Order article via Infotrieve]
4. Ginsberg MD, Lin B, Morikawa E, Dietrich WD, Busto R, Globus MY. Calcium antagonists in the treatment of experimental cerebral ischemia. Arzneimittelforschung. 1991;41:334–337.[Medline] [Order article via Infotrieve]
5. Ridenour TR, Warner DS, Todd MM, Baker MT. Effects of ketamine on outcome from temporary middle cerebral artery occlusion in the spontaneously hypertensive rat. Brain Res. 1991;565:116–122.[Medline] [Order article via Infotrieve]
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7. Crisostomo EA, Duncan PW, Propst M, Dawson DV, Davis JN. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol. 1988;23:94–97.
8. Feeney DM. From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients. In: Freund H-J, Sabel BA, Witte OW, eds. Brain Plasticity: Advances in Neurology. Philadelphia, Pa: Lippincott-Raven Publishers; 1997:383–394.
9. Feeney DM. Rehabilitation pharmacology: noradrenergic enhancement of physical therapy. In: Ginsberg MD, Bogousslavsky J. eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. Vol I. Cambridge, Mass: Blackwell Scientific Press; 1988:620–636.
10. Feeney DM. Mechanisms of noradrenergic modulation of physical therapy: effects on functional recovery after cortical injury. In: Goldstein LB, ed. Restorative Neurology: Advances in the Pharmacology of Recovery After Stroke. Armonc, NY: Futura Publishing Co Inc; 1988:35–78.
11. Stroemer, RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery following neocortical infarction in rats. Stroke. 1995;26:2135–2144.
12. Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke. 1998;29:2381–2393.
13. Feeney DM. Editorial comment on "Enhanced neurocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats." Stroke.. 1998;29:2393–2395.
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