Does femoral component loosening predispose to femoral fracture?: an in vitro comparison of cemented hips.

The incidence of femur fracture around total hip arthroplasties continues to increase at substantial cost to society. These fractures are frequently associated with a loose femoral component. Consequently, we sought to test whether femoral component loosening predisposes to periprosthetic femoral fracture. Because many periprosthetic femoral fractures are spiral in nature, we evaluated the torsional characteristics of the implanted femur in which the only design variable was instability of the femoral component. We used synthetic (polyurethane) (n = 15) and paired cadaveric femora (n = 10) with specimens divided into two groups: well-fixed and loose cemented stems. Each specimen was tested mechanically in internal rotation until failure. For the synthetic specimens, torque to failure was reduced by 38%, whereas stiffness was decreased 54% for the loose group compared with the well-fixed group. For the cadaveric specimens, torque to failure was reduced by 58%, whereas stiffness decreased 70% for the loose group compared with the well-fixed group. Fracture patterns were similar between synthetic and cadaveric femora with a proximal spiral pattern in loose specimens and more distal fracture patterns with well-fixed stems. Based on our data, patients with loosened femoral components are at risk for fracture at a substantially lower torque than those with well-fixed components.

Biomedical devices in meniscal repair.

Preservation of the menisci is increasingly emphasized in orthopedic care of the knee. Techniques are rapidly emerging that allow easier accomplishment of this goal. In particular, the development of all-inside arthroscopic meniscal repair devices has facilitated more ready repair. A number of laboratory and clinical studies have examined these devices and comparisons with more traditional techniques have been made. Numerous reports of potential complications from these new technologies have also been described in the literature. This review covers the current options for treatment of meniscal repair, laboratory and clinical data, and also potential complications.

Corticosterone increases damage and cytosolic calcium accumulation associated with ethanol withdrawal in rat hippocampal slice cultures.

BACKGROUND: Evidence suggests that stress hormones (i.e., glucocorticoids) may be increased during acute or chronic consumption of ethanol and during withdrawal from ethanol consumption, effects that may contribute to the development of cognitive impairment. The goal of the current studies was to examine the hypothesis that increased glucocorticoid levels in conjunction with ethanol exposure and withdrawal may cause hippocampal damage. METHODS: Organotypic hippocampal slice cultures were exposed to 50 mM ethanol for 10 days and withdrawn for 1 day. After withdrawal, cytotoxicity and cytosolic Ca2+ accumulation were measured using the nucleic acid stain propidium iodide and Calcium Orange, AM, respectively. Cultures were also treated with nontoxic concentrations of corticosterone (0.001-1 microM) during ethanol exposure and withdrawal or only during withdrawal. Additional cultures were coexposed to corticosterone and RU486 (0.1-10.0 microM), spironolactone (0.1-10.0 microM), or MK-801 (20 microM) during ethanol exposure and/or withdrawal. RESULTS: Ethanol withdrawal did not increase propidium iodide fluorescence and cytosolic Ca2+ levels. However, significant increases in propidium iodide fluorescence and in cytosolic Ca2+ accumulation were observed in cultures when corticosterone (> or = 100 nM) was exposed during ethanol treatment and/or withdrawal. These effects of corticosterone on ethanol withdrawal were attenuated by RU486 and MK-801 but not by spironolactone coexposure. CONCLUSIONS: This report demonstrated that corticosterone exposure during ethanol treatment and/or withdrawal resulted in significant hippocampal damage, possibly via activation of glucocorticoid receptors and enhancement of the glutamatergic cascade. The findings from these studies suggest that glucocorticoids contribute to the neuropathological consequences of alcohol dependence in humans.

Cytotoxic effects of exposure to the human immunodeficiency virus type 1 protein Tat in the hippocampus are enhanced by prior ethanol treatment.

BACKGROUND: Long-term ethanol exposure leads to increases in the expression and/or sensitivity of NMDA-type glutamate receptors, effects that may contribute to the development of cytotoxicity in the brain. The human immunodeficiency virus 1 (HIV-1) transcription factor Tat is one of many viral proteins that may contribute to the development of HIV-associated dementia (HAD) by indirectly or directly promoting excess function of NMDA receptors. Thus, these studies examined the hypothesis that long-term ethanol pre-exposure would sensitize the hippocampus to Tat-induced cytotoxicity in an NMDA receptor-dependent manner. METHODS: Organotypic slice cultures of rat hippocampus were exposed to a recombinant 86-amino acid form of Tat (Tat1-86) or a Tat deletion mutant devoid of amino acids 31 to 61 (TatDelta31-61; 0.1-100 nM) for 24 hr alone or during withdrawal from 10 days of ethanol exposure (50 mM in culture medium). Additional cultures were exposed to NMDA (5 microM) or the NMDA receptor channel blocker MK-801 (1 microM) during these treatments. Cellular injury in the CA1, CA3, and dentate gyrus regions of slice cultures was assessed by microscopy of propidium iodide fluorescence. RESULTS: Twenty-four hours of withdrawal from ethanol exposure did not produce overt cellular injury in any region of slice cultures. However, NMDA-induced toxicity was markedly increased in ethanol-pre-exposed cultures, an effect prevented by MK-801 (1 microM) coexposure. Treatment of cultures with Tat1-86 alone (> or = 0.1 nM) produced modest toxicity in each region of hippocampal cultures that was also blocked by MK-801 coexposure. In contrast, exposure to TatDelta31-61 did not alter propidium iodide fluorescence. Exposure of cultures to Tat1-86 (> or = 0.1 nM) during ethanol withdrawal resulted in a marked potentiation of Tat's toxic effects in each region of slice cultures, particularly the CA1 region. This potentiation of Tat neurotoxicity was significantly attenuated by coexposure of cultures to MK-801 (1 microM). CONCLUSIONS: These results indicate that long-term ethanol exposure sensitizes the hippocampus to the cytotoxic effects of Tat in an NMDA receptor-dependent manner. This may suggest that HIV-1-positive individuals who are alcohol dependent possess a heightened risk for the development of HAD. Furthermore, the NMDA receptor, particularly allosteric modulatory sites such as polyamine-sensitive sites, may be a therapeutic target to be investigated in the treatment of HAD.

Choline exposure reduces potentiation of N-methyl-D-aspartate toxicity by corticosterone in the developing hippocampus.

Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the alpha7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1-10 mM), prior to a brief (1 h) NMDA exposure (5 microM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (> or =1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the alpha7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.

Dynamic confirmation of fixation techniques of the tibial tubercle osteotomy.

The tibial tubercle osteotomy is gaining popularity for revision total knee arthroplasty; however, the potential for tubercle displacement has been a concern. This study compared the mechanical behavior of the tibial tubercle osteotomy after screw and cerclage wire fixation. Tibial tubercle osteotomy was done on 40 tibias from cadavers with equal numbers fixed by either screws or wires. Specimens were loaded cyclically to simulate straight leg raises and then loaded to failure with the patellar tendon oriented 0 degrees or 25 degrees from the tibial axis. Tibial tubercle osteotomy cyclic displacement was greater for wire constructs at 25 degrees than all other constructs. Failure loads were greater for screw constructs at 25 degrees than both wire constructs. Screw constructs failed at 1429 +/- 348 N (0 degrees) and at 1925 +/- 982 N (25 degrees). Wire constructs failed at 1072 +/- 260 N (0 degrees) and at 893 +/- 293 N (25 degrees). Bone mineral density correlated positively with failure loads. Straight leg raise (400 N) and knee extension (250 N) against gravity during rehabilitation should be feasible with either screw or wire fixation after tibial tubercle osteotomy. Special care should be taken for the large patient and patients with decreased bone density.

The human immunodeficiency virus type-1 transcription factor Tat produces elevations in intracellular Ca2+ that require function of an N-methyl-D-aspartate receptor polyamine-sensitive site.

Human immunodeficiency virus type-1 (HIV-1) infection is commonly associated with neuronal loss, as well as, cognitive and motor deficits collectively termed HIV-1-associated dementia (HAD). Function of the HIV-1 transcription factor Tat, activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, and subsequent rapid rises in free intracellular Ca2+ have been implicated in the development of this neurological disorder. However, the role of specific NMDA receptor modulatory sites in mediating effects of Tat has not been examined. The present studies examined the ability of two variants of Tat protein (1-100 nM), Tat 1-72 and Tat 1-86, to produce rapid rises in intracellular Ca2+ in organotypic slice cultures of rat hippocampus. Further, these studies evaluated the role of an NMDA receptor polyamine-sensitive site in mediating Tat-induced elevations in intracellular Ca2+. Brief exposure (10 min) to each variant of Tat protein (>1 nM) markedly increased levels of intracellular Ca2+ in each region of the hippocampus to as much as 145% of controls. In contrast, exposure of cultures to a deletion mutant of Tat protein devoid of amino acids 31-61 (Tat Delta31-61) did not produce changes in intracellular Ca2+ levels. Most significantly, exposure to the NMDA receptor antagonist dizocilpine (MK801 20 microM) and the polyamine site antagonist arcaine (10 microM) significantly attenuated increases in intracellular Ca2+ levels when co-administered with either the Tat 1-72 or Tat 1-86 amino acid variant of Tat. Thus, exposure of the hippocampus to Tat produces increases in intracellular Ca2+ levels that require function of an NMDA receptor polyamine-sensitive site and this may well contribute to the neurotoxic effects of HIV-1 infection. Polyamine-sensitive portions of this receptor may then represent novel therapeutic targets in the pharmacologic treatment of HAD-related neurotoxicity.

Opposing effects of ethanol and nicotine on hippocampal calbindin-D28k expression.

Long-term ethanol exposure produces multiple neuroadaptations that likely contribute to dysregulation of Ca(2+) balance and neurotoxicity during ethanol withdrawal. Conversely, nicotine exposure may reduce the neurotoxic consequences of Ca(2+) dysregulation, putatively through up-regulation of the Ca(2+)-buffering protein calbindin-D(28k). The current studies were designed to examine the extent to which 10-day ethanol exposure and withdrawal altered calbindin-D(28k) expression in rat hippocampus. Further, in these studies, we examined the ability of nicotine, through action at alpha(7)(*)-bearing nicotinic acetylcholine receptors (nAChRs), to antagonize the effects of ethanol exposure on calbindin-D(28k) expression. Organotypic cultures of rat hippocampus were exposed to ethanol (50-100 mM) for 10 days. Additional cultures were exposed to 500 nM (-)-nicotine with or without the addition of 50 mM ethanol, 100 nM methyllycaconitine (an alpha(7)*-bearing nAChR antagonist), or both. Prolonged exposure to ethanol (>/=50 mM) produced significant reductions of calbindin-D(28k) immunolabeling in all regions of the hippocampal formation, even at nontoxic concentrations of ethanol. Calbindin-D(28k) expression levels returned to near-control levels after 72 h of withdrawal from 10-day ethanol exposure. Extended (-)-nicotine exposure produced significant elevations in calbindin-D(28k) expression levels that were prevented by methyllycaconitine co-exposure. Co-exposure of cultures to (-)-nicotine with ethanol resulted in an attenuation of ethanol-induced reductions in calbindin-D(28k) expression levels. These findings support the suggestion that long-term ethanol exposure reduces the neuronal capacity to buffer accumulated Ca(2+) in a reversible manner, an effect that likely contributes to withdrawal-induced neurotoxicity. Further, long-term exposure to (-)-nicotine enhances calbindin-D(28k) expression in an alpha(7)* nAChR-dependent manner and antagonizes the effects of ethanol on calbindin-D(28k) expression.

The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between metabotropic glutamate type 5 receptors and N-methyl-D-aspartate receptors.

BACKGROUND: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. RESULTS: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. CONCLUSIONS: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Polyamines contribute to ethanol withdrawal-induced neurotoxicity in rat hippocampal slice cultures through interactions with the NMDA receptor.

BACKGROUND: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity. METHODS: Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1-100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 microM) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured. RESULTS: Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC(50) = 14.9 nM), arcaine (IC(50) = 37.9 nM), agmatine (IC(50) = 41.5 nM), and DFMO (IC(50) = 0.6 nM). NMDA (5 microM) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity. CONCLUSIONS: These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions.

Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors.

BACKGROUND: Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD-induced neurotoxicity in organotypic hippocampal slice cultures. METHODS: A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-D-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N-acetyl homotaurine or Na-acamprosate). A comparison of the effects of 100 microM guanosine 5'-triphosphate on unlabeled glutamate, trans-ACPD, and Na-acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 microM -ACPD or 50 microM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone. RESULTS: Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD. The presence of 100 microM guanosine 5'-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-acamprosate. Na-acamprosate (200-1000 microM) and SIB-1893 (20-500 microM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity. CONCLUSIONS: Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.

Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil.

Ifenprodil, arcaine and agmatine have all been reported to inhibit the NMDA receptor by actions at polyamine-sites, however the specific sites with which these compounds interact is unknown. Here we used radioligand binding of [3H]MK-801 to a membrane preparation from rat cerebral cortex to investigate the interactions of these compounds with the NMDA receptor complex. In the absence of exogenous polyamines, agmatine reduced [3H]MK-801 binding only at concentrations over 500 micro M, as opposed to the putative polyamine-site antagonists arcaine and ifenprodil which directly reduce ligand binding at much lower concentrations (5 micro M) in the absence of polyamines. In our studies, all three compounds significantly reduced spermidine-potentiated [3H]MK-801 binding, however agmatine was the only compound effective at concentrations below those that produced direct inhibition of [3H]MK-801 binding. Under these conditions, agmatine had a K(i)=14.8 micro M for spermidine-potentiated [3H]MK-801 binding and displayed characteristics of a competitive antagonist. Agmatine, as well as ifenprodil and arcaine, also displaced [3H]spermidine from rat cortical membranes at concentrations similar to those that were effective at reducing spermidine-potentiated [3H]MK-801 binding. In conclusion, these data suggest that agmatine reduces the potentiating effects of polyamines by competitive antagonism at a specific site on the NMDA receptor complex, and that these actions of agmatine differ from those of ifenprodil and arcaine.

Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus.

BACKGROUND: The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on -methyl-D-aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for potentiation of NMDAR function during ethanol withdrawal, we evaluated the effects of acamprosate, MK-801, and ifenprodil in a cell culture model of ethanol withdrawal-induced neurotoxicity. METHODS: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in vitro for 23 days before experimental use. The ethanol withdrawal model consisted of exposing cultures to ethanol (70-100 mM) for 4 days before being "withdrawn" into Calcium-Locke's buffer for 1 hr and then into minimal medium for 23 hr. Uptake of (45)CaCl(2) and propidium iodide by damaged cells was assessed 1 hr and 24 hr after the start of ethanol withdrawal, respectively. Additional studies examined effects of exposure to NMDA (50 microM) or spermidine (100 microM) on withdrawal-induced hippocampal damage. Last, these studies examined the ability of the sodium salt of acamprosate (Na-acamprosate, 200 microM), ifenprodil (50 microM), or MK-801 (30 microM) to inhibit neurotoxicity and (45)Ca(2+) entry produced by these insults. RESULTS: Ethanol withdrawal was associated with significantly greater toxicity and (45)Ca(2+) entry, relative to controls. Exposure to spermidine and NMDA during ethanol withdrawal further increased neurotoxicity and (45)Ca(2+) entry. Acamprosate, ifenprodil, and MK-801 almost completely prevented ethanol withdrawal-induced toxicity and (45)Ca(2+) entry. Acamprosate also reduced spermidine-induced neurotoxicity during ethanol withdrawal but was ineffective against NMDA-induced toxicity or (45)Ca(2+) entry at this time. CONCLUSIONS: The results support the contention that acamprosate, like ifenprodil, interacts with polyamines and that these compounds may be effective in reducing consequences of ethanol withdrawal. NMDAR activation is also strongly implicated in ethanol withdrawal neurotoxicity, but whether acamprosate causes any of these effects in this preparation directly via the NMDAR remains uncertain.

Acamprosate has no effect on NMDA-induced toxicity but reduces toxicity induced by spermidine or by changing the medium in organotypic hippocampal slice cultures from rat.

BACKGROUND: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures. METHODS: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 microM) alone or on neurotoxic challenges induced by either 50 microM NMDA or 100 microM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge. RESULTS: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced "basal" propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK-801; 30 microM) and, to a lesser extent, with ifenprodil (50 microM). Acamprosate did not significantly potentiate or inhibit NMDA-induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine-induced neurotoxicity. CONCLUSION: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA-induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine-mediated effects.