Video Illustrating Transient Reinstatement of Hemiplegic Symptoms In "Recovered"
Rats by Blockade of alpha 1-Noradrenergic Synaptic Transmission
Reinstatement of Symptoms
After unilateral ablation, trauma, or an infarct involving the sensorimotor
cortex there is a hemiplegia that "spontaneously" recovers in one or two
weeks in the rat and is best seen by having the animal attempt to traverse
a narrow beam. The hemiplegic animal fails to place the contralateral
limbs on the surface of the beam, especially the hindlimb. During
locomotion by hemiplegic animals the contralateral hindlimb is dragged
while beam walking is accomplished primarily by using the ipsilateral limbs.
This video illustrates the importance of alpha 1-Noradrenergic (NA)
transmission for maintaining recovery of function following cortical damage.
After an animal has recovered from hemiplegic symptoms produced by sensorimotor
cortex injury this "recovered state" is vulnerable to disruption by blockade
of alpha 1-NA activity. The initial symptoms can be transiently reinstated
by certain drugs in the recovered rat at least 6 months after " recovery".
Administration of selective alpha 1-NA receptor antagonists, such as phenoxybenzamine
or prazosin (shown in the video) or by clonidine, an alpha 2-NA agonist
which also reduces NA release, all transiently reinstate hemiplegic symptoms.
This video initally shows a "recovered" rat four months after focal sensorimotor
cortex contusion displaying normal beam walking performance. The
video then shows reinstatement of symptoms in this "recovered" rat after
receiving 4 mg/kg (i.p.) of prazosin. Within 30 minutes after prazosin
administration, the rat who had recovered from all hemiplegic symptoms
four months earlier does not place the contralateral limbs on the beam
surface (especially the hindlimb) during locomotion as do "recovered" or
normal rats. The hemiplegia observed during the first weeks after
injury that had "recovered" three-four months earlier, reappears for 2-3
hours. A low dose (2 mg/kg) of prazosin has little effect on beam
walking in normal rats but reinstates hemiplegia in recovered injured animals.
In normal animals higher doses of prazosin may disrupt beam walking but
have bilateral effects quite unlike hemiplegia. The unilateral symptoms
illustrated in this video are typical of reinstatement of hemiplegic deficits
in recovered rats. Reinstatement is not due to a nonspecific soporific
drug effect since the deficits reappear only in the limbs contralateral
to the cortical injury, and do not occur after a sedating dose of pentobarbital.
The reinstatement by alpha 1-NA does not weaken with time after injury
as expected. Dose-response studies show no difference in degree of
reinstatement at 1-6 months after injury. The degree of reinstatement
is highly correlated with the severity of the initial deficit (for the
high dose of prazosin and beam walk reinstatement scores at 1 month after
injury; r = .99). These data clearly indicate that recovery of some
symptoms is a fragile state for a prolonged time after symptoms are no
longer apparent. Lastly, when these drugs are administered early
(one day in the rat) after brain injury, they also slow spontaneous recovery.
The data describing these effects are reported in publications from different
laboratories listed in the references below (1, 2, 3, 4). Reinstatement
has been reported in several species and has implications for the selection
of drugs in the management of symptoms in patients with brain injury from
stroke or trauma. I thank Debra Stibick for assistance in making this video.
Importance for patients with brain damage from stroke or cerebral trauma
After patients are admitted to a hospital for stroke, clonidine, prazosin,
and other drugs, reported harmful for recovery from hemiplegia in laboratory
studies, are frequently prescribed for other medical problems such as hypertension
(5). The adverse effects on recovery of these and other drugs reported
in laboratory studies have also been described for recovery in hemiplegic
stroke patients (6) and also slow recovery of aphasia (7, 8). This
data and the mechanisms involved in both the beneficial and harmful effects
of NA on functional recovery has been reviewed (9, 10).
References
1. Feeney, D.M. and Westerberg, V. S. Norepinephrine and brain damage:
Alpha noradrenergic pharmacology alters functional recovery after cortical
trauma. Canadian Journal of Psychology, 1990,
44, 233-252.
2. Sutton, R.L. and Feeney, D.M. Alpha-noradrenergic agonists and antagonists
affect recovery and maintenance of beam-walking ability after sensorimotor
cortex ablation in the rat. Restorative Neurology and Neuroscience, 4,
1-11, 1992.
3. Feeney, D.M. From laboratory to clinic: Noradrenergic Enhancement
of Physical Therapy for Stroke or Trauma patients. In Freund, H.-J., Sabel,
B.A. and Witte, O.W., (Editors) Brain Plasticity; Advances in Neurology,
73, pg. 383-394, Lippencott-Raven Publishers, Philadelphia, 1997.
4. Goldstein LB, Davis JN. Clonidine impairs recovery of beam-walking
after a sensorimotor cortex lesion in the rat. Brain Res 1990;508:305-309
5. Goldstein, LB, Davis,JN Physician prescribing patterns
following hospital admission for ischemic cerebrovascular disease.
Neurology, 1988,38;1806-1899.
6. Goldstein LB, SASS Study Investigators. Common drugs
may influence motor recovery after stroke. Neurology 1995;45:865-871
7. Porch BE, Feeney DM. Effects of antihypertensive drugs
on recovery from aphasia. Proc Clin Aphasia Conf 1986;16:309-314.
8. Feeney, D.M. From laboratory to clinic: Noradrenergic Enhancement
of Physical Therapy for Stroke or Trauma patients. In Freund, H.-J., Sabel,
B.A. and Witte, O.W., (Editors) Brain Plasticity; Advances in Neurology,
73, pg. 383-394, Lippencott-Raven Publishers, Philadelphia, 1997.
9. Feeney, D.M., Pharmacologic Modulation of recovery after brain
injury: a reconsideration of diaschisis. Journal of Neurologic Rehabilitation,
5, 113-128, 1991.
10. Feeney, D. M. Rehabilitation Pharmacology: Noradrenergic
Enhancement of Physical Therapy. In: Ginsberg, M. and Bogousslavsky,
J. (Editors) Cerebrovascular Diseases, Vol. I. Blackwell Scientific Press
Cambridge MA (In Press.).