Effects of amphetamines and small related molecules on recovery after stroke in animals and man

doi:10.1016/S0028-3908(99)00249-X

Neuropharmacology

Volume 39, Issue 5, April 2000, Pages 852-859

https://doi.org/10.1016/S0028-3908(99)00249-X Get rights and content

Abstract

Drugs modulating the levels of specific central neurotransmitters may influence both the rate and amount of functional recovery after focal brain injuries such as stroke. Because such drugs may be effective long after brain injury, the “therapeutic window” may be widened beyond the first few hour after stroke and an entirely new avenue for pharmacological intervention may be possible. The impact of drugs affecting norepinephrine and γ-aminobutyric acid have been among the most extensively studied in the laboratory, and preliminary clinical data suggest similar effects in humans.

Introduction

Studies in laboratory animals are leading to novel approaches designed to enhance poststroke recovery. New methods of retraining stroke patients such as “forced use” are now being tested in humans (Ostendorf and Wolf, 1981, Taub et al., 1993, Miltner et al., 1999). The potential benefits of a variety of growth factors (Walsh et al., 1994, Kawamata et al., 1997) are being explored and the transplantation of progenitor cells is being investigated (Gage et al., 1995). Another potential avenue of therapy is derived from observations in laboratory animals that certain classes of drugs affecting the levels of specific central neurotransmitters can influence both the rate and ultimate amount of functional recovery after injury to the cerebral cortex (Feeney, 1997, Goldstein, 1993, Goldstein, 1997b). Preliminary clinical studies suggest that similar drug effects occur in humans recovering from stroke (Crisostomo et al., 1988, Walker-Batson et al., 1995, Goldstein et al., 1990, Goldstein, 1995). Although the influence of these drugs on neurological function can often be measured within hours of administration, their impact is prolonged. These observations suggest that relatively rapid drug-induced physiological changes are followed by a long-lasting functional reorganization.

Section snippets

Sympathomimetic amines and related drugs

In a seminal series of experiments, Feeney and coworkers found that, when combined with task-relevant experience, a single dose of d-amphetamine given 24 hr following unilateral sensorimotor cortex ablation in the rat resulted in an enduring enhancement of motor recovery (Feeney et al., 1982). This amphetamine effect extends to functional deficits that occur following focal lesions produced through a variety of mechanisms including ischemic brain injury, to lesions affecting other areas of the

Possible mechanisms of neurotransmitter-modulated recovery

As early as Feeney's original observations (Feeney et al., 1982), it was noted that an improvement in motor function in hemiplegic rats could be measured within one hour after receiving a single dose of amphetamine. This observation suggests that amphetamine has a rapid physiological effect that underlies this initial benefit. Feeney had hypothesized that drugs such as amphetamine might facilitate recovery by reversing the “remote functional depression” of brain regions distant from the site of

Enhancement of recovery

The first study of amphetamine's effects on recovery after stroke in humans was carefully designed to simulate the paradigm used in the laboratory. Eight patients with stable motor deficits were randomized to receive either 10 mg of amphetamine or placebo within 10 days of ischemic stroke (Crisostomo et al., 1988). Within three hours of drug administration, all of the patients underwent intensive physical therapy (i.e., drug administration was coupled with task-specific experience). The

Conclusion

These data suggest a consistent effect of drugs affecting central neurotransmitters on functional recovery after focal brain injury in laboratory animal models and in humans recovering from stroke. Although it is reasonable to avoid drugs suspected of impairing recovery when alternatives are available, the available data does not yet conclusively demonstrate a beneficial clinical effect of drugs such as amphetamine. Enthusiasm for the routine use of these drugs should continue to be restrained

References (117)

V.A. Aroniadou et al.
The role of NMDA receptors in long-term potentiation (LTP) and depression (LTD) in rat visual cortex
Brain Res.
(1991)
T.V.P. Bliss et al.
What is the mechanism of long-term potentiation in the hippocampus?
T.I.N.S.
(1982)
M.G. Boyeson et al.
Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury
Pharmacol. Biochem. Behav.
(1990)
M.G. Boyeson et al.
Unilateral, but not bilateral, locus coeruleus lesions facilitate recovery from sensorimotor cortex injury
Pharmacol. Biochem. Behav.
(1992)
S. Brailowsky et al.
γ-aminobutyric acid-induced potentiation of cortical hemiplegia
Brain Res.
(1986)
S. Brailowsky et al.
Phenytoin increases the severity of cortical hemiplegia in rats
Brain Res.
(1986)
B.M. Cohen et al.
In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action
Life Sci.
(1986)
D. Corbett
Long term potentiation of lateral hypothalamic self-stimulation following parabrachial lesions in the rat
Brain Res. Bull.
(1980)
D. Dahl et al.
Beta-Adrenergic agonist induced long-lasting synaptic modifications in hippocampal dentate gyrus require activation of NMDA receptors, but not electrical activation of afferents
Brain Res.
(1990)
J.N. Davis et al.
Brain alpha-adrenergic receptors: comparison of [3H]WB4101 binding with norepinephrine-stimulated cyclic AMP accumulation in rat cerebral cortex
Brain Res.
(1978)

R.M. Douglas et al.

Inhibitory modulation of long-term potentiation: evidence for a postsynaptic locus of control

Brain Res.

(1982)

D.M. Feeney et al.

Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation

Brain Res.

(1985)

M. Fiorelli et al.

PET studies of cortical diaschisis in patients with motor hemi-neglect

J. Neurol. Sci.

(1991)

L.B. Goldstein et al.

Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury

Pharmacol. Biochem. Behav.

(1997)

L.B. Goldstein et al.

Clonidine impairs recovery of beam-walking in rats

Brain Res.

(1990)

C. Grade et al.

Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study

Arch. Phys. Med. Rehabil.

(1998)

T.D. Hernandez et al.

Disruption of behavioral recovery by the anti-convulsant phenobarbital

Brain Res.

(1994)

D.A. Hovda et al.

Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat

Brain Res.

(1984)

R.M.A. Jaspers et al.

Local as well as remote functional and metabolic changes after focal ischemia in cats

Brain Res. Bull.

(1990)

T.A. Jones et al.

Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage

Brain Res.

(1992)

A.E. Kline et al.

Methylphenidate treatment following ablation-induced hemiplegia in rat: Experience during drug action alters effects on recovery of function

Pharmacol. Biochem. Behav.

(1994)

L.W. Lazarus et al.

Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison

Arch. Phys. Med. Rehabil.

(1994)

J.R. Lipsey et al.

Nortriptyline treatment of post-stroke depression: a double-blind study

Lancet

(1984)

S.J. Peroutka et al.

Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain

Neuropharmacology

(1977)

S. Roffler-Tarlov et al.

Effects of acute and chronic administration of desmethylimipramine on the content of norepinephrine and other monamines in the rat brain

Biochem. Pharmacol.

(1973)

T. Schallert et al.

Recovery of function after brain damage: Severe and chronic disruption by diazepam

Brain Res.

(1986)

M.L. Albert et al.

Pharmacotherapy for aphasia

Neurology

(1988)

A. Artola et al.

NMDA receptors and developmental plasticity in visual neocortex

D.L. Bachman et al.

The role of pharmacotherapy in the treatment of aphasia

Aphasiology

(1988)

T.V.P. Bliss et al.

Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path

J. Physiol.

(1973)

T.V.P. Bliss et al.

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

(1973)

J.V. Bowler et al.

Contribution of diaschisis to the clinical deficit in human cerebral infarction

Stroke

(1995)

M.G. Boyeson et al.

Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4

Behav. Neurosci.

(1992)

M.G. Boyeson et al.

Effects of trazodone and desipramine on motor recovery in brain-injured rats

Am. J. Phys. Med. Rehabil.

(1993)

M.G. Boyeson et al.

Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury

Am. J. Phys. Med. Rehabil.

(1994)

Y. Cao et al.

Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis

Stroke

(1998)

Y. Castella et al.

Acute thrombotic infarction suppresses metabolic activation of ipsilateral somatosensory cortex: evidence for functional diaschisis

J. Cereb. Blood Flow Metab.

(1989)

F. Chollet et al.

The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography

Ann. Neurol.

(1991)

S.C. Cramer et al.

A functional MRI study of subjects recovered from hemiparetic stroke

Stroke

(1997)

E.A. Crisostomo et al.

Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients

Ann. Neurol.

(1988)

T.J. Crow

Cortical synapses and reinforcement: a hypothesis

Nature

(1968)

D. Dahl et al.

Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus

Proc. Natl. Acad. Sci., USA

(1989)

M. Dam et al.

Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy

Stroke

(1996)

W.D. Dietrich et al.

Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain

Stroke

(1990)

R.M. Douglas et al.

Commissural inhibition and facilitation of granule cell discharge in fascia dentata

J. Comp. Neurol.

(1983)

G.L. Dunbar et al.

d-Amphetamine attenuates learning and motor deficits following cortical injury in rats

Soc. Neurosci. Abstr.

(1989)

D.M. Feeney

Pharmacologic modulation of recovery after brain injury: a reconsideration of diaschisis

J. Neuro. Rehab.

(1991)

D.M. Feeney

From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients

D.M. Feeney et al.

Amphetamine, haloperidol, and experience interact to affect the rate of recovery after motor cortex injury

Science

(1982)

D.M. Feeney et al.

Pharmacotherapy for recovery of function after brain injury

CRC Crit. Rev. Neurobiol.

(1987)

Cited by (93)

Neuroimaging of stroke recovery from aphasia – Insights into plasticity of the human language network
2019, NeuroImage
Citation Excerpt :
Importantly, it should be noted that acetylcholinesterase inhibitors such as donepezil are usually not given in patients with normal cognitive functions but rather used for treatment of Alzheimer's Disease to slow deterioration of cognitive functions (see Marsh and Hillis, 2006). Nevertheless, short- and long-term safety and tolerability has been demonstrated in patients with post-stroke aphasia (see Berthier et al., 2011 or Llano and Small, 2016 for review) and acetylcholinesterase inhibitors may have positive effects on recovery during language rehabilitation (e.g. Berthier et al., 2003; Berthier et al., 2014; Goldstein, 1999, 2000). Other pharmacological treatments that might prove beneficial in aphasia recovery include the noncompetitive N-methyl-d-aspartate receptor antagonist memantine that modulates glutamergic activity and might augment synaptic plasticity in spared language regions (Berthier et al., 2009), and potentially the γ aminobutyric acid derivative piracetam, at least in the acute phase after stroke (e.g. Kessler et al., 2000; see above).
The role of left and right hemisphere brain regions in language recovery after stroke-induced aphasia remains controversial. Here, we summarize how neuroimaging studies increase the current understanding of functional interactions, reorganization and plasticity in the language network. We first discuss the temporal dynamics across the time course of language recovery, with a main focus on longitudinal studies from the acute to the chronic phase after stroke. These studies show that the functional contribution of perilesional and spared left hemisphere as well as contralesional right hemisphere regions to language recovery changes over time. The second section introduces critical variables and recent advances on early prediction of subsequent outcome. In the third section, we outline how multi-method approaches that combine neuroimaging techniques with non-invasive brain stimulation elucidate mechanisms of plasticity and reorganization in the language network. These approaches provide novel insights into general mechanisms of plasticity in the language network and might ultimately support recovery processes during speech and language therapy. Finally, the neurobiological correlates of therapy-induced plasticity are discussed. We argue that future studies should integrate individualized approaches that might vary the combination of language therapy with specific non-invasive brain stimulation protocols across the time course of recovery. The way forward will include the combination of such approaches with large data sets obtained from multicentre studies.
Pharmacological Treatment of Visuospatial Neglect: A Systematic Review
2017, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
We excluded studies in which attention deficits were treated, based on the lack of outcome measures aimed at the VSN syndrome. In fact, several human studies used pharmacotherapy as a treatment of attention and cognitive impairments after stroke.62-68 For example, both Jorge et al and Adams and Robinson found that anti-depressives may enhance motor and cognitive recovery after stroke.66,67
The aims of the current review were (1) to give an overview of human studies investigating pharmacotherapy to ameliorate visuospatial neglect and (2) to evaluate the quality of those studies.
A systematic literature search using PubMed, Scopus, and ResearchGate was conducted in regard to studies that evaluated pharmacological interventions aiming to ameliorate poststroke visuospatial neglect. The search was limited in the following features: species (human), adults (≥18 years of age), language (English), and type of neglect (visuospatial). Two independent authors extracted data on study content and effectiveness and evaluated the quality of studies and methods.
A total of 11 studies were identified. Three studies were considered to be of moderate quality, the others of low quality. Seven studies represented dopaminergic treatment; 3 studies represented cholinergic treatment; and 1 study represented noradrenergic treatment. Three dopaminergic studies showed primarily positive effects of dopaminergic stimulation on visuospatial neglect, whereas three others showed adverse effects. All 3 cholinergic studies found positive effects in some outcome measures concerning visuospatial neglect. Noradrenergic stimulation improved maintenance of attention when exploring space.
Currently, cholinergic therapy might be the best option for future research. However, we must emphasize the explorative nature and the limited quality of the reviewed studies.
Sensorimotor recovery from cortical injury is accompanied by changes on norepinephrine and serotonin levels in the dentate gyrus and pons
2016, Behavioural Brain Research
Monoamines such as norepinephrine (NE) and serotonin (5-HT) have shown to play an important role in motor recovery after brain injury. The effects elicited by these neurotransmitters have been reported as distal from the area directly affected. Remote changes may take place over minutes to weeks and play an important role in post-stroke recovery. However, the mechanisms involved in spontaneous recovery have not been thoroughly delineated. Therefore, we determined the NE and 5-HT content, in the pons and hippocampal dentate gyrus (DG) as well as motor deficit and spontaneous activity in rats after 3, 10 and 20 days cortical iron injection. Three days post-lesion the pontine NE content diminished, this effect was accompanied by deficient spontaneous activity and impaired sensorimotor evaluation. Ten and twenty days after lesion the NE levels were similar to those of control group, and animals also showed behavioral recovery. Monoamines content on DG 3 days post-lesion showed no differences as compared to controls. Interestingly, ten and twenty days after cortical injury, animals showed increased NE and 5-HT. These results suggest that behavioral recovery after brain damage involve changes on monoamines levels on DG, an important structure to plastic processes. In addition, the results herein support evidence to propose these neurotransmitters as key molecules to functional recovery in the central nervous system.
Pharmacological interventions in traumatic brain injury: Can we rely on systematic reviews for evidence?
2016, Injury
Citation Excerpt :
Dopaminergic agonists (DA) are a distinct group of drugs within the class of monoaminergic agonists and include bromocriptine. It has been proposed that these drugs may aid in functional recovery of the brain and prevent permanent loss-of-function following traumatic brain injury [35–37]. Sutton [38] suggested that MAs lead to “metabolic normalisation” of dysfunctional, but still viable neurons in the area surrounding the injury.
Providing current, reliable and evidence based information for clinicians and researchers in a synthesised and summarised way can be challenging particularly in the area of traumatic brain injury where a vast number of reviews exists. These reviews vary in their methodological quality and are scattered across varying sources. In this paper, we present an overview of systematic reviews that evaluate the pharmacological interventions in traumatic brain injury (TBI). By doing this, we aim to evaluate the existing evidence for improved outcomes in TBI with pharmacological interventions, and to identify gaps in the literature to inform future research.
We searched the Neurotrauma Evidence Map on systematic reviews relating to pharmacological interventions for managing TBI in acute phase. Two reviewers independently screened search results and appraised each systematic review using the validated AMSTAR tool and extracted data from the review.
A total of 288 systematic reviews relating to TBI were available on the Neurotrauma Evidence Map at the time of this study. We identified 19 systematic reviews on pharmacological management for acute TBI with publications dates ranging from 1998 to 2014. The studies were of varying methodological quality, with a mean AMSTAR score of 7.78 (range 2–11].
The evidence from high quality systematic reviews show that there is currently insufficient evidence for the use of magnesium, monoaminergic and dopamine agonists, progesterone, aminosteroids, excitatory amino acid inhibitors, haemostatic and antifibrinolytic drugs in TBI. Anti-convulsants are only effective in reducing early seizures with no significant difference between phenytoin and leviteracetam. There is no difference between propofol and midazolam for sedation in TBI patients and ketamine may not cause increased ICP. Overviews of systematic review provide informative and powerful summaries of evidence based research.
Pharmacotherapy for Aphasia
2015, Neurobiology of Language
There are no currently approved drug therapies to assist in the recovery from aphasia. However, there is suggestive evidence from the animal literature that behavioral training, coupled with pharmacotherapy, can enhance recovery from motor stroke. Most of the pharmacologic interventions used in these studies involved sympathomimetic drugs, although other mechanisms were used as well, such enhancement in cholinergic signaling. A number of studies have been performed using human patients with aphasia. These studies are also suggestive of enhancement in recovery when sympathomimetic drugs are used in conjunction with speech and language therapy. There are also data to support cholinesterase inhibitors memantine and piracetam. In addition, other drugs, such as barbiturates, antipsychotics, and anticonvulsants, may slow recovery. Although more work is needed, these studies, which are critically reviewed herein, suggest that thoughtful use of pharmacologic agents in conjunction with speech and language therapy can enhance recovery from aphasic stroke.
GABAergic but not anti-cholinergic agents re-induce clinical deficits after stroke
2010, Journal of the Neurological Sciences
Our goal was to determine whether the excitatory (i.e., GABA) neurotransmitter system was important in human stroke recovery. We hypothesized that giving midazolam, a GABA_A agonist, to patients would re-induce clinical deficits to a greater extent than the anti-cholinergic scopolamine. Twelve patients (7 M) who had recovered from hemiparesis and/or aphasia after first-time stroke and 10 age-matched, healthy controls underwent double-blinded drug challenge with midazolam and 90 days later with scopolamine, or vice versa. Language was scored for comprehension, naming and repetition, and motor function was tested with the 9-Hole Peg Test (9HPT) in each hand. The drugs were administered intravenously in small aliquots until mild awake sedation was achieved. The primary outcome was the change scores from baseline to the two drug conditions, with higher scores denoting greater loss of function. Ten of the 12 patients had recovered from hemiparesis and 7 from aphasia. The median time from stroke to participation was 9.3 months (range = 0.3–77.9 months). For motor function, analysis of variance showed that change scores on the 9HPT were significantly greater in patients using the previously paretic hand during the drug state with midazolam (p = 0.001). Similarly, language change scores were significantly greater among recovered aphasics during the midazolam challenge (p = 0.01). In our study, patients demonstrated transient re-emergence of former stroke deficits during midazolam but not scopolamine. These data provide beginning clinical evidence for the specificity of GABA-sensitive pathways for stroke recovery.

View all citing articles on Scopus

View full text

Published by Elsevier Ltd.

Effects of amphetamines and small related molecules on recovery after stroke in animals and man

Abstract

Introduction

Section snippets

Sympathomimetic amines and related drugs

Possible mechanisms of neurotransmitter-modulated recovery

Enhancement of recovery

Conclusion

Brain Res.

T.I.N.S.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Res.

Brain Res.

Life Sci.

Brain Res. Bull.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

J. Neurol. Sci.

Pharmacol. Biochem. Behav.

Brain Res.

Arch. Phys. Med. Rehabil.

Brain Res.

Brain Res.

Brain Res. Bull.

Brain Res.

Pharmacol. Biochem. Behav.

Arch. Phys. Med. Rehabil.

Lancet

Neuropharmacology

Biochem. Pharmacol.

Brain Res.

Pharmacotherapy for aphasia

Neurology

NMDA receptors and developmental plasticity in visual neocortex

The role of pharmacotherapy in the treatment of aphasia

Aphasiology

Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Contribution of diaschisis to the clinical deficit in human cerebral infarction

Stroke

Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4

Behav. Neurosci.

Effects of trazodone and desipramine on motor recovery in brain-injured rats

Am. J. Phys. Med. Rehabil.

Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury

Am. J. Phys. Med. Rehabil.

Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis

Stroke

Acute thrombotic infarction suppresses metabolic activation of ipsilateral somatosensory cortex: evidence for functional diaschisis

J. Cereb. Blood Flow Metab.

The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography

Ann. Neurol.

A functional MRI study of subjects recovered from hemiparetic stroke

Stroke

Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients

Ann. Neurol.

Cortical synapses and reinforcement: a hypothesis

Nature

Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus

Proc. Natl. Acad. Sci., USA

Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy

Stroke

Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain

Stroke

Commissural inhibition and facilitation of granule cell discharge in fascia dentata

J. Comp. Neurol.

d-Amphetamine attenuates learning and motor deficits following cortical injury in rats

Soc. Neurosci. Abstr.

Pharmacologic modulation of recovery after brain injury: a reconsideration of diaschisis

J. Neuro. Rehab.

From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients

Amphetamine, haloperidol, and experience interact to affect the rate of recovery after motor cortex injury

Science

Pharmacotherapy for recovery of function after brain injury

CRC Crit. Rev. Neurobiol.