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Biomedical subjects

D G Stein

Publications and source records attributed to D G Stein.

At least 19 recordsLinked to original sources
PubMed2004

Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex.

We compared the effects of three different doses of allopregnanolone (4, 8 or 16 mg/kg), a metabolite of progesterone, to progesterone (16 mg/kg) in adult rats with controlled cortical impact to the pre-frontal cortex. Injections were given 1 h, 6 h and every day for 5 consecutive days after the injury. One day after injury, both progesterone-treated (16 mg/kg) and allopregnanolone (8 or 16 mg/kg)-treated rats showed less caspase-3 activity, and rats treated with allopregnanolone (16 mg/kg) showed less DNA fragmentation in the lesion area, indicating reduced apoptosis. Nineteen days after the injury, rats treated with progesterone and allopregnanolone (8 or 16 mg/kg) showed no difference in necrotic cavity size but had less cell loss in the medio-dorsal nucleus of the thalamus and less learning and memory impairments compared with the injured vehicle-treated rats. On that same day the injured rats treated with progesterone showed more weight gain compared with the injured rats treated with the vehicle. These results can be taken to show that progesterone and allopregnanolone have similar neuroprotective effects after traumatic brain injury, but allopregnanolone appears to be more potent than progesterone in facilitating CNS repair.

Animals↗
PubMed2001

Biocompatibility of methylcellulose-based constructs designed for intracerebral gelation following experimental traumatic brain injury.

Tissue engineering in the post-injury brain represents a promising option for cellular replacement and rescue, providing a cell scaffold for either transplanted or resident cells. We have characterized the use of methylcellulose (MC) as a scaffolding material, whose concentration and solvent were varied to manipulate its physical properties. MC solutions were produced to exhibit low viscosity at 23 degrees C and form a soft gel at 37 degrees C, thereby making MC attractive for minimally invasive procedures in vivo. Degradation and swelling studies in vitro demonstrated a small amount of initial polymer erosion followed by relative polymer stability over the 2-week period tested as well as increased hydrogel mass due to solvent uptake. Concentrations up to 8% did not elicit cell death in primary rat astrocytes or neurons at 1 or 7 days. Acellular 2% MC (30 microl) was microinjected into the brains of rats 1 week after cortical impact injury (velocity = 3 m/s, depth = 2 mm) and examined at 2 days (n = 8; n = 3, vehicle injected) and 2 weeks (n = 5; n = 3, vehicle injected). The presence of MC did not alter the size of the injury cavity or change the patterns of gliosis as compared to injured, vehicle-injected rats (detected using antibodies against GFAP and ED1). Collectively, these data indicate that MC is well suited as a biocompatible injectable scaffold for the repair of defects in the brain.

Animals↗
PubMed2001

Brain damage, sex hormones and recovery: a new role for progesterone and estrogen?

Estrogen and progesterone, long considered for their roles as primary hormones in reproductive and maternal behavior, are now being studied as neuroprotective and neuroregenerative agents in stroke and traumatic brain injuries. Collectively, the hormones reduce the consequences of the injury cascade by enhancing anti-oxidant mechanisms, reducing excitotoxicity (altering glutamate receptor activity, reducing immune inflammation, providing neurotrophic support, stimulating axonal remyelinization), and enhancing synaptogenesis and dendritic arborization. Estrogen seems more effective as a prophylactic treatment in females at risk for cardiac and ischemic brain injury, whereas progesterone appears to be more helpful in the post-injury treatment of both male and female subjects with acute traumatic brain damage. However, a recent clinical trial with estradiol replacement therapy in elderly women that have a history of cerebrovascular disease, showed that this hormone was unable to protect against reoccurrence of ischemia or to reduce the incidence of mortality compared to a placebo.

Animals↗
PubMed2001

Serum progesterone levels correlate with decreased cerebral edema after traumatic brain injury in male rats.

Previous animal research suggests that progesterone may have powerful neuroprotective effects in traumatic brain injury (TBI). This experiment tested the hypothesis that progesterone levels correlate with decreased cerebral edema in male rats with bilateral medial frontal cortex injuries. Three groups of male Sprague-Dawley rats were used: injured given progesterone (4 mg/kg), injured given vehicle (oil), and uninjured controls given vehicle. Progesterone or vehicle was administered intraperitoneally at 1, 6, and 24 h postinjury. At 48 h postinjury, the rats were killed, brains extracted, and assayed for edema. Percent difference in water content of the area surrounding the lesion was compared to posterior cortex. A strong inverse relationship was found between serum progesterone levels and percent cerebral edema; the higher the progesterone levels, the lower the percent edema. Both progesterone and oil-treated animals had some edema compared to sham-operated controls. The brains of the injured animals given control solution were higher in water content than either the uninjured group or injured progesterone-treated rats 48 h postinjury. These findings confirm that progesterone significantly decreases cerebral edema after TBI in adult male subjects.

Animals↗
PubMed2001

Behavioral and morphological consequences of primary astrocytes transplanted into the rat cortex immediately after nucleus basalis ibotenic lesion.

Adult male rats received transplants of dissociated 30-day old cultured cortical astrocytes into the ipsilateral frontal and parietal cortex immediately after unilateral ibotenic acid lesion of the NBM or after sham injury. We hypothesized that transplants of astrocytes into the acetylcholine-deprived cortex might provide trophic support to terminals arising from damaged NBM neurons. Twenty four hours after transplantation and every other day for 11 days post surgery, the animals were tested for locomotion and habituation in an open field. NBM lesion reduced vertical movements only as compared to no lesion and no transplant counterparts. Nine days after surgery rats with NBM lesion and astrocyte-transplants into the cortex were as impaired in the acquisition of a passive avoidance (PA) task as untreated counterparts. Animals with no lesions and transplants into the cortex also had significant PA acquisition deficits. All rats with ibotenic lesion were significantly impaired on PA retention as compared to rats with no lesions. Astrocyte-transplants survived up to 2 months after cortical implantation but these transplants produced severe laminar disruption and gliosis. This effect was greater in rats with NBM lesion than in intact animals with transplants into the cortex. These data show that astrocyte-transplants do not promote functional recovery after NBM lesion and suggest an immune rejection of the astrocyte transplants by the host brain.

Acetylcholine↗
PubMed2001

Effects of the duration of progesterone treatment on the resolution of cerebral edema induced by cortical contusions in rats.

UNLABELLED: PURPOSE. The aim of the present study was to assess the effect of different durations of administration of progesterone (4 mg/kg) on the resolution of edema 6 days after medial frontal cortex contusions (MFC) in male adult rats. METHODS: Animals sustaining injury were injected with progesterone or its vehicle for 3 days or for 5 days beginning the first hour after surgery. On the 6th day the rats were killed and their brain water content was measured. RESULTS: We confirmed the presence of edema six days after MFC. However, both 3 and 5 days of treatment with progesterone significantly reduced edema in the injured brains but the five days of treatment were more effective. The effects of progesterone depend upon the duration of the treatment because there are two waves of edema. The first phase begins within a few hours of the injury and the second starts several days later. CONCLUSIONS: Our data are consistent with earlier findings showing that longer durations of progesterone administration lead to more complete behavioral recovery as well as to an increased number of surviving neurons.

Acute Disease↗
PubMed2000

Does endogenous progesterone promote recovery of chronic sensorimotor deficits following contusion to the forelimb representation of the sensorimotor cortex?

We studied sensorimotor recovery in male, normal-cycling and pseudopregnant female rats following unilateral FL-SMC contusions. Forelimb use (push off before a rear, support against the walls, and landing after a rear) and the foot fault test (foot misplacements during locomotion on an elevated grid) were analyzed from videotapes taken before surgery, and then again on post-surgical days 2 and 36. High endogenous progesterone levels in females at the time of injury did not affect recovery as there were no differences between males, pseudopregnant females and normal-cycling female rats on these behaviors. None of the brain-injured rats recovered symmetrical forelimb use between 2 and 36 days after injury (P>0.05) and they also showed foot misplacements (P>0.05) in the foot fault test. Male and female rats with contusions had fewer mean foot misplacements on day 36 than 2 days after injury (P<0.001), indicating that there was partial recovery on this task. These results were taken to show that there were no sex differences in motor deficits caused by unilateral FL-SMC injury. In addition, higher endogenous progesterone levels in females did not protect them from the chronic sensorimotor deficits caused by unilateral FL-SMC contusions.

Animals↗
PubMed2000

Effects of the novel NMDA receptor antagonist gacyclidine on recovery from medial frontal cortex contusion injury in rats.

Gacyclidine, a novel, noncompetitive NMDA receptor antagonist, was injected (i.v.) into rats at three different doses to determine if the drug could promote behavioral recovery and reduce the behavioral and anatomical impairments that occur after bilateral contusions of the medial frontal cortex (MFC). In the Morris water maze, contused rats treated with gacyclidine at a dosage of 0.1 mg/kg performed better than their vehicle-treated conspecifics. Rats given gacyclidine at either 0.3 or 0.03 mg/kg performed better than brain-injured controls, but not as well as those treated with 0.1 mg/kg. Counts of surviving neurons in the nucleus basalis magnocellularis (NBM) and the medial dorsal nucleus (MDN) of the thalamus were used to determine whether gacyclidine treatment attenuated secondary cell death. In both the NBM and the MDN, the counts revealed fewer surviving neurons in untreated contused rats than in gacyclidine-treated rats. Increases in the size and number of microglia and astrocytes were observed in the striatum of gacyclidine-treated contused brains. Although most consequences of MFC contusions were attenuated, we still observed increases in ventricle dilation and thinning of the cortex. In fact, the ventricles of rats treated with 0.1 mg/kg of gacyclidine were larger than those of their vehicle treated counterparts, although we observed no behavioral impairment.

Animals↗
PubMed1999

Regional changes in the expression of neurotrophic factors and their receptors following acute traumatic brain injury in the adult rat brain.

We have analyzed the effect of severe traumatic brain injury (TBI) on the levels of mRNA expression of neurotrophic factors (NTFs): brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and their respective receptors: trkB, trkA and CNTFRalpha. The expression was examined in the region of the lesion as well as a region remote from the lesion at 12, 24, and 36 h following the injury. Our data suggest that after the brain injury, the expression of NGF and BDNF mRNAs were early, transiently and significantly upregulated while that of CNTF was a slow and less amplified response in both areas of the brain. We also found that trkA mRNA expression was only upregulated significantly in the remote area; trkB mRNA showed no significant change in either area except an upregulation at 12 h in the remote area. CNTFRalpha was downregulated significantly by 24-36 h in the lesion area and by 24 h in the remote area. These changes suggest that TBI regulates the expression of NTFs and their receptors. These alterations in expression may be involved in modulating the neuronal response after brain injury.

Age Factors↗
PubMed1999

Effects of unilateral entorhinal cortex lesion on retention of water maze performance.

In a previous study, adult male Sprague-Dawley rats with unilateral, electrolytic entorhinal cortex lesions showed significant deficits in acquisition of a water maze task that measured working memory. The 10 days of testing used two trials per day with an intertrial interval of 1 h, and the rats with entorhinal damage were impaired in total distance to the platform in both trials. In the present retention study, rats who learned the same task prior to injury and were then retested for 5 days after lesion showed only a first day deficit in total distance to platform in the second trial. Analysis of swim patterns indicated that rats with unilateral entorhinal lesions used an altered strategy in retention testing to find the platform in the second trial of each day and incorporated the use of headings appropriate for Trial 1 only. This altered or compensatory strategy was not the optimum choice for problem solution. Although the rats then were able to switch headings and find the platform without significant impairment in total distance to platform on days 2-5 of testing, the use of an initial incorrect strategy indicated subtle residual deficits in cue integration and use of working memory.

Animals↗
PubMed1999

GM1 produces attenuation of short-term memory deficits in Hebb-Williams maze performance after unilateral entorhinal cortex lesions.

The Hebb-Williams maze was used to examine spatial abilities of adult male Sprague-Dawley rats with unilateral electrolytic entorhinal cortex lesions. The injured rats were treated for 14 days with either saline or ganglioside GM1. Testing was begun 7 weeks following injury, and involved 12 maze problems with independent configurations, with immediate starting replacement used for the six trials per problem. Compared to sham-operated counterparts, the rats with lesion plus saline treatment were impaired in total number of errors, initial entry errors, and repeat errors over 12 consecutive problems. GM1-treated rats showed improved performance, making significantly fewer total and repeat errors, indicating that this substance may be potentially useful as therapy after entorhinal cortex injury.

Analysis of Variance↗
PubMed1998

Intraseptal injections of 192 IgG saporin produce deficits for strategy selection in spatial-memory tasks.

The involvement of the cholinergic septohippocampal system in strategies used to reach a spatial goal was examined by functionally inactivating this system with infusions of 192 IgG saporin, a potent cholinergic immunotoxin. Rats were initially trained on a win-shift radial arm maze (RAM) task and then given injections of either 192 IgG saporin (LES) or saline vehicle (CON) into the medial septum and vertical limb of the diagonal band. Rats were then retested postoperatively on the RAM to assess whether allocentric spatial strategies used to solve the task were impaired. The results indicated that injections of 192 IgG saporin into the septum of rats produced deficits in allocentric strategies used to locate the spatial goal when retested. In addition, place and response learning was also examined in a modified version of the Morris water maze task. In this task, rats with cholinergic lesions were mildly impaired in their ability to learn a place response. In order to clarify further whether rats may have been relying on allocentric or egocentric learning strategies to locate the platform, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both an allocentric and egocentric response. However, rats with the cholinergic septal lesions swam to the new platform location indicating an egocentric response. Taken together, these results suggest that selective cholinergic lesions of the septum produce deficits in spatial strategies used to locate a spatial goal.

Animals↗
PubMed1998

Acute ethanol administration reduces the cognitive deficits associated with traumatic brain injury in rats.

The present study was designed to determine whether a low dose of acute ethanol administration could attenuate cognitive deficits associated with traumatic brain injury. Adult male rats received oral administration of ethanol or drinking water 2 h prior to surgery to produce a blood ethanol concentration of 100 mg% and then received bilateral contusion injuries of the medial prefrontal cortex. Seven days after surgery, the rats began 10 days of testing for acquisition of spatial localization in the Morris water maze where they were required to find a hidden platform to escape from the water. The results indicate that the rats given ethanol at the time of injury later spent significantly less time searching for the hidden platform than their water-treated counterparts. On a memory probe test given on the final day of testing, in which the platform was removed from the pool, rats given the ethanol spent more time in the area where the platform had been located indicating that they learned its location better than the lesion/water controls. In addition, acute ethanol treatment reduced some of the histopathology that typically occurs following severe contusion of the medial frontal cortex but did not attenuate post-traumatic formation of edema. These results indicate that acute ethanol intoxication can reduce the severity of cognitive impairments caused by contusive traumatic brain injury and support the contention that there is a dose-response relationship of acute ethanol intoxication in the setting of traumatic brain injury.

Animals↗
PubMed1997

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.

Animals↗
PubMed1997

Progesterone protects against lipid peroxidation following traumatic brain injury in rats.

The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone's attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone's effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone's possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.

Animals↗
PubMed1997

Effects of a single intraseptal injection of NGF on spatial learning in the water maze.

Male Sprague-Dawley rats given electrolytic lesions of the septum followed by a single intraseptal injection of 5 microg of NGF were trained on a water maze task that assessed their ability to learn the location of a visible platform and the location of platform when it was submerged. Rats with damage to the septum acquired the visible platform version of the task but were significantly impaired in locating the submerged platform. Administration of NGF, however, produced an intermediate ameliorative effect on the measure of latency to find the hidden platform during these trials. In order to determine the relative strength of the place and cue responses learned during the visible and hidden platform training trials, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both a place and cue response. However, both rats with septal damage alone and rats with septal lesions treated with NGF swam directly to the new platform location indicating the relative strength of the cue response. These results support previous findings indicating that a single injection of NGF can produce improvements on a cognitive task, but it may not be doing so by restoring lost spatial functions following septohippocampal damage.

Acetylcholinesterase↗
PubMed1997

Persistent short term memory deficits in Hebb-Williams maze performance are shown by rats with unilateral entorhinal cortex lesions.

The spatial abilities of adult, male Sprague-Dawley rats in the Hebb-Williams maze were examined at 6 months after unilateral electrolytic entorhinal cortex lesions. Compared with sham-operated rats, their performance was impaired in both initial entry and repeat entry errors over 12 consecutive problems, using immediate starting replacement for the 6 trials per problem. The configurations of the 12 maze problems are independent, and deficits were seen over the entire course of the testing. This study indicates that Hebb-Williams maze performance deficits after unilateral entorhinal cortex lesion are persistent and can be seen up to 6 months after injury.

Animals↗