Norepinephrine and brain damage: Alpha noradrenergic pharmacology alters functional recovery after cortical trauma.

Abstract

The goal of (hese experiments was to evaluate the effects of some drugs affecting noradrencrgic (NE) synaptic transmission, commonly prescribed following stroke or traumatic brain injury, on functional recovery. Measurement of recovery from a transient hcmiplegia produced by a traumatic unilateral ft>cal contusion in sensorimotor cortex (SMCX) of rats was used to assess the effects of chronic haloperidol (HAL) treatment begun early (I day) or late (18 days to recovered animals) after injury. Additionally, using the same model, the effects of a single administration of drugs with selective action at NP. receptors were also evaluated early or late (30 days) after injury. These drugs were: phenoxybenzamine (PBZ), an alpha,-NE antagonist; pra/.osin (PRAZ), an alpha,-NF. antagonist; yohimbine (YOH), an alpha 2 -NE antagonist; propranolol (PROP), a beta,-and 2 -NE receptor antagonist; methoxymine (METHOX), an alpha,-NE agonist; and elonidinc (CLON), an alpha 2 -NR agonist. The data indicate that drugs with antagonistic effects at alpha, NE receptors, including HAL and PRAZ but not PROP, administered early after SMCX contusion retard loeomotor recovery. Beneficial effects of enhancing NE transmission by METHOX or YOH were not observed. In animals recovered from beam walk (BW) deficits, a single administration of PBZ or PRAZ (alpha, NE antagonists) or CLON (alpha 2 NE agonist) transiently reinstated hemiplegic symptoms. The nonspecific beta NE receptor antagonist PROP had no effect in recovered animals. A single dose of HAL had no effect in recovered animals, but a BW deficit transiently developed in some animals following chronic treatment. The data are discussed with reference to drug contraindications noted in clinical studies of recovery from poststroke aphasia and cognition in demented patients with degenerative brain disease.RF.SUMK Lc but de ces experiences etait d'cvaluer les effets dc quelques drogues ayant une action sur la transmission synaptique noradrencrgique (NE), ct qui sont commuriement prescrites apres une attaque ou une blessure cerebrale, sur la recuperation fonctionnellc. Dcs mesures de la recuperation d'une hemiplegic transitoire produitc chez. le rat par induction d'unc contusion traumatique unilateral locale dans lc cortex sensorimoteur ont ete utilisees pour evaluer les effets du traitement ehroniquca l'haloperidol (HAL) commence tot (I jour) ou tard (ISjours a la recuperation) apres la lesion. De plus, utilisant le memc mixlele, les effets d'une administration unique de drogues ayant une action selective sur les rcccpteurs NE ont etc aussi cvalues tot ct tard (30 jours) apres la lesion. Les drogues sont: phenoxybenzamine Considerable technical support is required lor the many aspects of the labour intensive drug screening studies ot functional recovery after cerebral trauma reported in this article. We thank Drs. R.I.. Sutton and M.S. Weaver for assistance in conducting some of these experiments and for training others to continue the experiments; L.J. Fanner, and T. Mores for work on the prazos...

Responses of cortical noradrenergic and somatostinergic fibres and terminals to adjacent strokes and subsequent treatment with NGF and/or the ganglioside GM1

“…area studied. This finding is in accordance with previous pharmacological and biochemical studies showing that the level of central cortical norepinephrine decreases after traumatic brain injury (Feeney and Westerberg, 1990;Goldstein and Davis, 1990;Prasad et al, 1994) or when the noradrenergic axons originating from the locus coeruleus are compromised (Carbary et al, 1996). The lesion used in the present study was an unilateral devascularising lesion, which produces extensive ischemic cortical infarction and causes a gradual loss of the affected cortex and retrograde degeneration of nucleus basalis magnocellularis (NBM) cholinergic neurons (Sofroniew et al, 1983).…”

Improved neurological function after Amantadine treatment in two patients with brain injury

“…Increased attention recently has been directed towards the role of neurotransmitters in recovery from brain injury. Studies using animal models have shown that inhibition of norepinephrine, acetylcholine, serotonin and dopamine activity may limit recovery, whereas increased levels of these neurotransmitters may be linked to neurological improvement (2)(3)(4). Of these four neurotransmitters, the effects of dopamine are perhaps some of the most diverse.…”

Divergent Long-Term Consequences of Chronic Treatment with Haloperidol, Risperidone, and Bromocriptine on Traumatic Brain Injury–Induced Cognitive Deficits

“…HAL delayed motor recovery after brain injury when given as an acute 9,10 or chronic treatment paradigm. 11 Similarly, a single administration of various doses of HAL (0.1, 1.0, or 10.0 mg/kg) significantly impeded locomotor recovery when given to rats a day after sensorimotor cortex injury. 12 Aside from deleterious effects on motor performance, daily HAL treatment (15 days) after fluid percussion injury significantly delayed the acquisition of spatial learning in the Morris water maze (MWM), compared to injury alone.…”