The Effect of α-Adrenergic Receptor Blockers Prazosin and Yohimbine on Cerebral Metabolism and Biogenic Amine Content of Traumatized Brain

Abstract

Widespread decrease in local cerebral glucose utilization (LCGU) previously shown to occur 3 days after a local freezing lesion was interpreted as reflecting a depression of functional activity in the affected areas. In parallel experiments, cortical norepinephrine (NE) content of traumatized brain was found to be decreased. The effects of prazosin (PZ), an alpha 1-adrenergic receptor blocker, and yohimbine (YOH), an alpha 2-blocker, on glucose use and biogenic amine content of lesioned rat brain were studied to determine if the changes in the noradrenergic system associated with injury are of functional importance, to identify the receptors that may be involved in mediating the action of NE in injured brain, and to look for evidence of interaction between the noradrenergic and the serotonergic systems in traumatized brain. PZ (1 mg/kg) given 30 min before the lesion ameliorated the subsequent metabolic cortical depression seen in untreated animals. PZ given for 3 days starting before the lesion (3 mg/kg/day) was also effective in normalizing LCGU in areas where it was depressed by lesioning, despite the fact that this regimen induced significant global decrease in LCGU in normal animals. Once cortical metabolic depression had developed 3 days after the lesion, it could not be modified by PZ. YOH was less effective than PZ and was so only when given for 3 days (22.5 mg/kg/day in three divided doses). PZ (3 mg/kg/day in three divided doses) slightly but significantly decreased the accumulation of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid in the traumatized hemisphere. These results provide evidence that blockage of alpha 1-adrenergic receptors prevents the development of cortical dysfunction associated with brain trauma. This implies that the noradrenergic system plays a role in the functional consequences of injury and that this effect is, at least in part, mediated by alpha 1-adrenergic receptors. Furthermore, alpha 1-adrenergic receptor blockage appears to modulate cortical turnover of 5-HT, previously also implicated in functional consequences of brain injury. The data are compatible with inhibitory effects of NE in the cortex and suggest a potential of alpha 1-adrenergic blockage in development of novel therapeutic approaches to brain injury.

Cerebral Vascular Injury in Traumatic Brain Injury

“…Primary injury results from the physical impact causing direct biomechanical injury to cerebral tissues (neurons, glia and vessels). Secondary injury results from the molecular and cellular responses to the initial injury, resulting in a physiologic cascade that furthers neural injury (Besancon et al, 2008;Ellison et al, 1989;Golding et al, 1999;Inoue et al, 1991;Pappius et al, 1988). TCVI can result from both primary (blunt force) and secondary injury (e.g.…”

Phosphodiesterase‐5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury

“…Multiple pharmacologic and non‐pharmacologic therapies with well‐established medical indications promote blood vessel repair and may prove beneficial as therapy for TCVI in appropriately selected patients 27, 28, 29, 30. Sildenafil is a potent and specific inhibitor of cGMP‐specific phosphodiesterase (Phosphodiesterase 5, PDE5), thereby prolonging the elevation of cGMP resulting from the induction of guanylyl cyclase by nitric oxide (NO).…”

Alpha-Adrenoceptor Modulation in Central Nervous System Trauma: Pain, Spasms, and Paralysis - An Unlucky Triad

“…In this study, the functional state of the traumatized brain was assessed with the deoxyglucose method, which is based on the finding that cortical depression of glucose utilization is correlated with somatosensory deficits. 90 There are no changes in α2-AR expression reported after TBI. 78,81,82,91 Stimulating α2-ARs negatively affects locomotion recovery after TBI.…”

“…In contrast, the study by Inoue et al indicates that blocking α1‐ARs prevents somatosensory deficits associated with brain trauma. In this study, the functional state of the traumatized brain was assessed with the deoxyglucose method, which is based on the finding that cortical depression of glucose utilization is correlated with somatosensory deficits …”