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PubMed1977

Ethanol potentiation of central nervous system trauma.

Two models have been used to study the effects of ethanol on injuries of the central nervous system. The spinal cords of cats were injured by delivering a 200 gm-cm impact to the exposed dura mater. A second group of animals received a similar injury to the exposed dura mater overlying the cerebral hemispheres. The animals were divided into two groups, those that received an infusion of ethanol before injury, and control animals that received no ethanol. The parameters of injury used in this model produced small and insignificant lesions in those animals that received no ethanol; however, when the animals were pretreated with ethanol, a considerable increase in the extent of the injury was noted. These include alterations in membranes-bound enzymes and clotting mechanisms, and alteration of cell membranes through abnormal free radical reactions.

Animals↗
PubMed2005

Role of the cell cycle in the pathobiology of central nervous system trauma.

Upregulation of cell cycle proteins occurs in both mitotic and post-mitotic neural cells after central nervous system (CNS) injury in adult animals. In mitotic cells, such as astroglia and microglia, they induce proliferation, whereas in post-mitotic cells such as neurons they initiate caspase-related apoptosis. We recently reported that early central administration of the cell cycle inhibitor flavopiridol after experimental traumatic brain injury (TBI) significantly reduced lesion volume, scar formation and neuronal cell death, while promoting near complete behavioral recovery. Here we show that in primary neuronal or astrocyte cultures structurally different cell cycle inhibitors (flavopiridol, roscovitine, and olomoucine) significantly reduce upregulation of cell cycle proteins, attenuate neuronal cell death induced by etoposide, and decrease astrocyte proliferation. Flavopiridol, in a concentration dependent manner, also attenuates proliferation/activation of microglia. In addition, we demonstrate that central administration of flavopiridol improves functional outcome in dose-dependent manner after fluid percussion induced brain injury in rats. Moreover, delayed systemic administration of flavopiridol significantly reduces brain lesion volume and edema development after TBI. These data provide further support for the therapeutic potential of cell cycle inhibitors for the treatment of clinical CNS injury and that protective mechanisms likely include reduction of neuronal cell death, inhibition of glial proliferation and attenuation of microglial activation.

Animals↗
PubMed1997

5-aminocoumarans: dual inhibitors of lipid peroxidation and dopamine release with protective effects against central nervous system trauma and ischemia.

A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were developed for the treatment of traumatic and ischemic central nervous system (CNS) injury. Compounds within this class were extremely effective inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathecal injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compounds were tested for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranamine) exhibited potent effects in these assays (inhibition of lipid peroxidation, IC50 = 0.07 microM; mouse-FeCl2-it assay, ID50 = 10.4 mg/ kg, po; MAP-induced hypermotility, 98% inhibition, 10 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218), which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the survival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disorders in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 days after injury. These results imply a role for dopamine in deterioration of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is now under clinical investigation.

Animals↗
PubMed1987

A nonglucocorticoid steroid analog of methylprednisolone duplicates its high-dose pharmacology in models of central nervous system trauma and neuronal membrane damage.

Prior studies have demonstrated that intensive treatment with high doses of methylprednisolone (MP) can beneficially affect the acutely injured central nervous system by a variety of mechanisms and promote neurological recovery in experimentally injured animals. In view of the fact that these actions are associated only with MP doses greatly in excess of those required for classical glucocorticoid receptor-mediated actions of the steroid, the possibility was examined that this high-dose pharmacology of MP could be duplicated by a nonglucocorticoid analog. Accordingly, U-72099E (17,21-dihydroxy-11 alpha-t-butylacetoxy-1,4-pregnadiene-3,20-dione- 21-hemisuccinate, sodium salt) was synthesized and tested for its ability to duplicate the high-dose effects of MP in a concussive head injury model in mice and in an in vitro model of lipid peroxidation-induced membrane damage using rat brain synaptosomes. The absence of glucocorticoid-related activity of U-72099E was confirmed by its inability to either suppress body weight gain or cause thymic involution in mice treated with doses up to 100 mg/kg/day for 4 days. On the other hand, MP at 30 mg/kg/day for 4 days caused a complete inhibition of body weight gain and a 43.5% reduction in thymus weight. Moreover, U-72099E, at concentrations of 10(-5) M or lower, failed to suppress adrenocorticotropin secretion by mouse AtT-20 pituitary cells in culture, whereas dexamethasone or MP at concentrations of 10(-6) M and lower caused a marked suppression in adrenocorticotropin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1998

A prospective study of predictors of disability at 3 months after non-central nervous system trauma.

OBJECTIVE: To delineate which injury-related, demographic, and psychosocial variables were predictive of severe disability (limitations in the performance of socially defined roles and tasks) at 3 months after discharge from acute hospitalization for non-central nervous system traumatic injury. PATIENTS AND METHODS: The study design was prospective, longitudinal, and correlational. The sample consisted of 109 injured patients at three urban trauma centers. Data were obtained from patient interview using the Sickness Impact Profile, the Impact of Event Scale, and the Social Support Questionnaire; injury-related data were obtained from the medical record and computerized trauma registries. RESULTS: The sample had a mean age of 37.4 +/- 16.8 years, a mean number of injuries per person of 4.4 +/- 2.8, and a mean Injury Severity Score of 15.5 +/- 9.9. Motor vehicle crashes (34.9%) and violent injuries (33%) were the predominant causes of injuries. Patients experienced severe levels of disability (Sickness Impact Profile, mean = 26.1) and moderate levels of psychological distress (Impact of Event Scale, mean = 30.6; intrusion mean = 14.6 and avoidance mean = 16.0). Three variables were predictive of severe disability at 3 months: high levels of intrusive thoughts (odds ratio, 2.9; 95% confidence interval, 1.1-7.7); injury with a maximal Abbreviated Injury Scale score in an extremity (odds ratio, 2.9; 95% confidence interval, 1.2-6.9); and having not graduated from high school (odds ratio, 3.4; 95% confidence interval, 1.2-10). CONCLUSION: Extremity injuries, lack of high school graduation, and high level of posttraumatic psychological distress with intrusive thoughts are risk factors for severe disability at 3 months after discharge from the hospital.

Activities of Daily Living↗
PubMed1985

Septic complications of corticosteroid administration after central nervous system trauma.

The records of 197 consecutive multiple trauma patients were reviewed to define the infectious complications of corticosteroids used to treat brain and spinal cord injury. An injury severity score (ISS) and a central nervous system (CNS) injury score were determined for each patient. Patients with an ISS less than 20 did well with or without steroids and were excluded from further study. All deaths that occurred 5 or more days after injury were caused by sepsis, and all occurred in steroid recipients. Twenty-nine of 61 steroid-treated early survivors developed infectious complications, compared to eight of 55 patients who did not receive steroids (47.5% vs. 14.5%, p less than 0.001). There was no correlation between severity of CNS trauma and infectious complication rate. Steroid-treated patients frequently developed multiple pathogen primary infections and multiple, simultaneous septic foci. Patients treated with steroids more often developed infections caused by Staphylococcus aureus, assorted gram negative rods, anerobic bacteria, or fungi. The study strongly suggests a significant increase in both the incidence and severity of infectious complications occurring in patients treated with corticosteroids for CNS trauma.

Adolescent↗
PubMed1995

Inhibition of lipid peroxidation in central nervous system trauma and ischemia.

A novel group of compounds, the 21-aminosteroids ("lazaroids"), have been designed that are potent inhibitors of oxygen free radical-induced, iron-catalyzed lipid peroxidation (LP) in microvascular and nervous tissue. One of these, tirilazad mesylate (U-74006F), has been selected for clinical evaluation as a cerebroprotective agent. In vitro studies suggest that tirilazad exerts its antioxidant activity by multiple mechanisms including: increasing membrane stability, scavenging of lipid peroxyl radicals, reducing LP-induced arachidonic acid release, decreased formation or scavenging of hydroxyl radicals, and maintenance of the levels of endogenous vitamin E. The major site of action appears to be the blood-brain barrier based upon its known localization in cerebrovascular endothelium and numerous studies showing an attenuation of subarachnoid hemorrhage (SAH), injury, and ischemia-induced blood-brain barrier permeability. Tirilazad has demonstrated neuroprotective efficacy in multiple preclinical models of spinal cord and head injury, SAH, and focal cerebral ischemia, as measured by a decrease in cerebral vasospasm, blood-brain barrier compromise, post-traumatic ischemia, edema, ischemic neuronal necrosis and infarction, and improved neurological recovery. This efficacy is correlated with a reduction in markers of oxygen radical-induced LP. Phase III clinical trials are currently ongoing in spinal cord and head injury, SAH, and ischemic stroke. Initial results from a European/Australian/New Zealand trial in SAH have shown a significant decrease in mortality and an increase in the incidence of good recovery.

Animals↗
PubMed1992

2-(Aminomethyl)chromans that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma and ischemia.

A series of 2-(aminomethyl)chromans was developed as potent inhibitors of iron-dependent lipid peroxidation. Compounds within this class are extremely effective at inhibiting lipid peroxidation with IC50's as low as 0.2 microM. Selected members were found to enhance early neurological recovery and survival in a mouse head injury model. In this assay, improvement in the 1-h post-head-injury neurological status (grip test score) by as much as 230% of control was observed. One of the most efficacious compounds (35) was evaluated in two models of cerebral ischemia where significant neuroprotection was observed. These results provide further support for the importance of cerebroprotective antioxidants for the treatment of traumatic and ischemic injury as well as additional evidence for the role of oxygen radicals in postischemic brain damage.

Animals↗
PubMed2002

Central nervous system trauma management of concussions in athletes.

The care of athletes with concussions is challenging because each patient has different symptoms. An athlete should never be returned to play until completely asymptomatic. Classification systems for concussions are not based on scientific evidence and represent some practitioners' best guess at what is safe for young athletes. Many experienced team physicians believe they can allow an athlete to play safely if there are no symptoms at rest and no symptoms with increasing intensity of exercise. Abbreviated neuropsychological testing and balance tests show promise for use in the field to increase the sensitivity of our neurological evaluation on injured athletes. Any neuropsychological or balance evaluation is more helpful if baseline data is collected on athletes before they are injured.

Adolescent↗
PubMed1995

2,3-Dihydro-1-benzofuran-5-ols as analogues of alpha-tocopherol that inhibit in vitro and ex vivo lipid autoxidation and protect mice against central nervous system trauma.

A series of alpha-tocopherol analogues was synthesized with potential therapeutic value for such pathological conditions as stroke and trauma. A set of criteria such as the inhibition of in vitro lipid peroxidation, superoxyl radical scavenging, and brain penetration, as measured by ex vivo inhibition of lipid peroxidation, was applied to select the most effective compound. 2,3-Dihydro-2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)methyl]-1 - benzofuran-5-ol dihydrochloride (22) was selected because of its superior antioxidant properties and better brain penetration. This compound also protected mice against the effects of head injury. The criteria thus turned out to be useful for the characterization of a neuroprotective analogue of alpha-tocopherol.

Animals↗
PubMed1990

Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 microM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha- methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

Amines↗