Stuart W. Hoffman

A reliable and sensitive enzyme immunoassay method for measuring 8-isoprostaglandin F2α: a marker for lipid peroxidation after experimental brain injury

The objectives of this study were to determine (1) if levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a non-enzymatically produced prostaglandin, were increased after cortical contusion and (2) if enzyme immunoassay (EIA) could be used to quantify 8-isoPGF2 alpha levels. 24 h after the contusion there was a significant rise in 8-isoPGF2 alpha compared to control levels. The levels returned to baseline by 72 h postinjury. The results show that this EIA method is a reliable and sensitive technique for measuring brain lipid peroxidation.

Effects of BIM-22015, an analog of ACTH4–10, on functional recovery after frontal cortex injury

Male rats, 90-100 days old, with frontal cortex lesions were given either subcutaneous sterile water (SW) as a vehicle control or 1, 10, or 100 micrograms of BIM-22015 every other day for 20 days. Brain-injured subjects tested in the Morris water maze with either 10 micrograms BIM-22015 or SW took significantly more trials than sham-operated rats to locate a submerged platform eight consecutive times within 60 s. The animals given 1 or 100 micrograms BIM-22015 took significantly fewer trials to reach criterion than brain-injured animals in the other drug treatment groups. On a percentage of savings, measured 8 days after reaching criterion, the brain-injured subjects given 1, 10, or 100 micrograms BIM-22015 did not differ from sham-operated rats. In contrast, the brain-injured animals given SW took longer to find the submerged platform than they did during the initial training. To assess long-term effects of the ACTH analog treatment, rats were trained on a delayed spatial alternation task 30 days after receiving the last injection. On this task, brain-injured rats treated with the 10-micrograms dose performed significantly better than those given sterile water. Acetylcholinesterase (AChE)-labeled neurons counted in the nucleus basalis magnocellularis indicated that rats with frontal cortex damage given the 10-micrograms treatment did not differ from the sham controls and had significantly more AChE-positive neurons than injured counterparts treated with SW or 100 micrograms.

Synaptic remodeling and free radical formation after brain contusion injury in the rat.

The purpose of this study was to explore whether bilateral frontal cortex contusion in rats would demonstrate changes relevant for understanding the pathology of frontal lobe injury in humans. Rats were allowed to survive for 3, 7, or 18 days postinjury (dpi). In the contused rats, albumin was trapped in frontal cortices, as well as in other brain areas, showing that neurons were exposed to plasma components. In the sham-operated rats, which had only craniotomy but no penetration of dura, the level of trapped albumin was also increased compared to intact controls, suggesting a partial lesion-like condition. Choline acetyltransferase activity was severely decreased in the frontal cortices of contused rats, compared to the sham-operated controls. The decrease was most pronounced at 3 dpi and less pronounced 18 dpi, suggesting that after the initial damage, regeneration of the cholinergic terminals occurred. The concentration of the mature presynaptic membrane protein D3(SNAP-25) was also decreased in the frontal cortices of contused rats at 3 and 7 dpi, whereas it was normalized at 18 dpi. Previously, we have evaluated changes in the rate of synaptic remodeling in brain injury by calculating the ratio of the neural cell adhesion molecule (NCAM) to D3(SNAP-25). The NCAM/D3(SNAP-25) ratio at 3 dpi was elevated by more than 60% in the frontal cortices of contused rats, suggesting a high initial rate of synaptic remodeling. The ratios were smaller at 7 and 18 dpi, suggesting that after the initial burst, the rate of remodeling leveled off. In contrast, astrocyte activation was less pronounced at 3 dpi than at 7 and 18 dpi, as measured by the levels of glial fibrillary acidic protein and glutamine synthetase immunoactivities. The immunoreactivity of glutamine synthetase more than doubled in the contused brains but its enzymatic activity increased less than 50%, suggesting that many enzymatic centers had been inactivated by free radicals. Calculated as the difference between the relative immunoreactivity and the relative enzymatic activity the lost glutamine synthetase activity increased continuously in frontal cortex and striatum from 3 to 18 dpi, indicating the production of free radicals long after the initial contusion event. In conclusion, following frontal cortical contusions the early synaptic damage was partly compensated by synaptic remodeling. We suggest that the continuous production of free radicals may have contributed to the declining remodeling rate and impair functional recovery.

Vaginocervical stimulation attenuates hindpaw shock-induced substance P release into spinal cord superfusates in rats.

The present study was designed to elucidate the mechanism in the spinal cord by which vaginocervical stimulation (VS) attenuates responses to noxious stimulation. This was accomplished by testing the hypothesis that VS reduces noxious stimulation-induced release of substance P at the level of the spinal cord. Noxious foot shock significantly increased the release of substance P (measured using radioimmunoassay) into superfusates of the lumbosacral spinal cord region in urethane-anesthetized rats. VS applied concurrently with foot shock significantly attenuated the release of substance P compared to the foot shock-only condition. In addition, substance P levels were significantly lower after the VS-only condition than after the no stimulation or foot shock-only conditions. These findings indicate that VS may produce analgesia, at least in part, by suppressing the release of substance P within the spinal cord.

Pharmacological treatments for brain-injury repair: Progress and prognosis

Abstract It has been only within the last 10 years that research on treatment for central nervous system (CNS) recovery after injury has become more focused on the complexities involved in promoting recovery from brain injury when the CNS is viewed as an integrated and dynamic system. There have been major advances in research in recovery over the last decade, including new information on the mechanics and genetics of metabolism and chemical activity, including the definition of excitotoxic effects and the discovery that the brain secretes complex proteins, peptides, and hormones that are capable of directly stimulating the repair of damaged neurons or blocking some of the degenerative processes caused by the injury cascade. Many of these agents, plus other non-toxic, naturally occurring substances, are being tested as treatment for brain injury. Further work is needed to determine appropriate combinations of treatments and optimum times of administration with respect to the time course of the CNS disorde...