The ability of a novel non-glucocorticoid 21-aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival.
The compound U-74006F is one of a series of 21-aminosteroids that lack glucocorticoid or mineralocorticoid activity. These potent inhibitors of lipid peroxidation have been specifically developed for the acute treatment of central nervous system trauma and ischemia. This study evaluated the dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord. Thirty minutes following injury, randomized and investigator-blinded treatment was initiated with the intravenous administration of either vehicle (citrate-buffered saline) or one of eight doses of U-74006F. Initial doses of U-74006F ranged from 0.01 to 30 mg/kg. Subsequent doses consisted of intravenous bolus injections followed by a continuous 42-hour intravenous infusion. Over the 48-hour treatment period, cats received total U-74006F doses ranging from 0.048 to 160 mg/kg. The animals were evaluated weekly for neurological recovery based upon an 11-point behavioral scale. With the exception of two cats in one group, the animals receiving accumulated doses of U-74006F (ranging from 1.6 to 160.0 mg/kg/48 hrs) exhibited nearly 75% of normal neurological function by 4 weeks after injury. Lower total doses of 0.16 and 0.48 mg/kg/48 hrs were associated with approximately 50% return of normal function, which was not significantly better than the recovery in the vehicle-treated control group. The lowest total dose tested (0.048 mg/kg/48 hrs) gave results indistinguishable from those in vehicle-treated cats, which had recovered only 20% of their preinjury neurological function by 4 weeks. These findings demonstrate that over a 100-fold range of doses, U-74006F has a remarkable capacity to promote functional recovery in spinal cord-injured cats.
A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
Numerous experimental studies of blunt spinal cord injury have shown that while a variable degree of immediate mechanical damage occurs to spinal blood vessels and axons in proportion to the magnitude of the injury force, a considerable amount of post-traumatic tissue degeneration is due to a secondary pathophysiological process that may be modifiable by appropriate therapeutic intervention. A growing body of biochemical, physiological, and pharmacological evidence has suggested that oxygen free radical-induced lipid peroxidation, working in concert with aberrant calcium fluxes and eicosanoid generation in particular, plays a key role in progressive post-traumatic spinal cord degeneration. Of particular importance, lipid peroxidation has been linked to microvascular damage and hypoperfusion which, if severe enough, can lead to a secondary ischemic insult to the tissue. The ability of intensive dosing with the glucocorticoid steroid methylprednisolone to beneficially affect post-traumatic ischemia and to promote chronic neurologic recovery in spinal cord injured animals has been correlated not with its glucocorticoid activity, but rather with the ability to inhibit post-traumatic spinal lipid peroxidation. In view of this, a novel series of non-glucocorticoid 21-aminosteroids has been developed which lack glucocorticoid activity but are more effective inhibitors of nervous tissue lipid peroxidation than the glucocorticoid steroids. One of these, U74006F, has now been studied in some detail and appears to be a promising new agent for the acute treatment of spinal cord (and brain) trauma. The background and pre-clinical development of this compound to date is reviewed.
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