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PubMed2003

Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies.

The proinflammatory cytokines tumor necrosis factor (TNFalpha), interleukin-1 (IL-1alpha), and interleukin-6 (IL-6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21-day-old male CD-1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule-1 (ICAM-1), glial fibrillary acidic protein (GFAP), anti-apoptotic TNFalpha-inducible early response gene (A-20), macrophage inflammatory protein (MIP)-1alpha, TNFalpha, IL-1alpha, IL-6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM-1, A-20, and TNFbeta elevations. Pentoxifylline blocked elevations in A-20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFalpha-neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT-induced elevations in mRNA levels for ICAM-1, A-20, GFAP, MIP-1alpha, IL-1alpha, TNFalpha, TNFbeta, and caspase 3 were blocked by anti-TNFalpha. These data demonstrate a significant role for TNFalpha in an acute neuro-injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB-22, a murine acute-phase response gene homologous to the alpha (1)-antichymotrypsin gene. Elevations were similar for artificial cerebral spinal fluid and anti-IL-1alpha, and significantly increased with anti-TNFalpha, anti-IL-6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFalpha in the pathogenesis of hippocampal injury induced by TMT.

Animals↗
PubMed2004

Interactions of alkyltin salts with biological dithiols: dealkylation and induction of a regular beta-turn structure in peptides.

Organotin compounds specifically target vicinal dithiols, thereby inhibiting the function of essential enzymes. Here, we present the NMR binding studies of trimethyltin (TMT) and dimethyltin (DMT) chlorides with a linear peptide (ILGCWCYLR) derived from the membrane protein stannin (SNN). We show that this peptide is able to dealkylate TMT and bind DMT, adopting a stable type-I beta-turn conformation. Both the NMR data and the calculated structures indicate that the two cysteines coordinate the tin atom in a distorted tetrahedral geometry. The molecular geometries and tin coordination state were confirmed using density functional theory (DFT). In addition, NMR spectral parameters back calculated from the DFT minimized structure compared well with experimental data. These results in conjunction with studies on peptide variants (i.e., C4S, C6S, and Y7F) demonstrate unequivocally the key role of biological dithiols in both the dealkylation and binding of organotin compounds. This peptide serves as a model system for alkyltin-protein interactions and gives new insights into the biological fate of alkyltin compounds.

Alkylation↗
PubMedDate not supplied

The toxicity and neuropathology of dimethylethyltin and methyldiethyltin in rats.

Triethyltin causes an increase in brain water with vacuolation of myelin sheaths, whereas trimethyltin is selectively damaging to neurons, especially of the hippocampal formations, causing chromatolysis, accumulation of cytoplasmic dense bodies and often cell death. The effects on rats of the analogues, dimethylethyltin and methyldiethyltin (oral LD50 14 mg/kg and 7.5-10.0 mg/kg respectively) are now reported. The dimethylethyl compound produces functional changes resembling those caused by trimethyltin, while the methyldiethyl compound causes responses similar to those produced by triethyltin. Structurally, however, the dimethylethyl compound, while producing marked nerve cell changes of the trimethyltin type also causes moderate vacuolation of myelin sheaths. By contrast, methyldiethyltin causes marked vacuolation of myelin sheaths of the triethyltin type and relatively minor neuronal changes of the trimethyltin type. These findings are discussed in terms of the structure-activity relationships of trialkyltin compounds.

Animals↗
PubMed1994

The neuroprotective effect of tacrine on trimethyltin induced memory and muscarinic receptor dysfunction in the rat.

In this study chronic (39 days) tacrine (3 mg/kg i.p.) treatment significantly improved trimethyltin (8 mg/kg i.p.) induced deficits in spatial navigation. Tacrine also reduced trimethyltin induced hyperactivity and passive avoidance deficits but these effects did not reach statistical significance. The effect of trimethyltin on muscarinic (M1 and M2) receptor sites was determined by means of quantitative autoradiography using [3H]quinuclidinyl benzilate. A selective pattern of M1 and M2 receptor loss was observed mainly affecting the hippocampus and other limbic structures while leaving other brain regions intact. Tacrine successfully prevented the M1 and M2 receptor loss in the CA1 and CA4 hippocampal subfields. The improvement in trimethyltin behavioural toxicity following tacrine treatment may be related to the protective effect of this compound on muscarinic receptor density in the hippocampal formation and lends support to the hypothesis that cholinergic system dysfunction may be primarily responsible for trimethyltin induced deficits in cognitive function.

Amino Acid Transport Systems, Neutral↗
PubMed2001

Biocompatibility of silicon-based arrays of electrodes coupled to organotypic hippocampal brain slice cultures.

In this study we examined the passive biocompatibility of a three-dimensional microelectrode array (MEA), designed to be coupled to organotypic brain slice cultures for multisite recording of electrophysiological signals. Hippocampal (and corticostriatal) brain slices from 1-week-old (and newborn) rats were grown for 4-8 weeks on the perforated silicon chips with silicon nitride surfaces and 40 microm sized holes and compared with corresponding tissue slices grown on conventional semiporous membranes. In terms of preservation of the basic cellular and connective organization, as visualized by Nissl staining, Timm sulphide silver-staining, microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) immunostaining, the slice cultures grown on chips did not differ from conventionally grown slice cultures. Neither were there any signs of astrogliosis or neurodegeneration around the upper recording part of the 47-microm-high platinum-tip electrodes. Slice cultures grown on a separate set of chips with platinum instead of silicon nitride surfaces also displayed normal MAP2 and GFAP immunostaining. The width of the GFAP-rich zone (glia limitans) at the bottom surface of the slice cultures was the same ( approximately 20 microm) in cultures grown on chips with silicon nitride and platinum surfaces and on conventional insert membranes. The slice cultures grown on chips maintained a normal, subfield differentiated susceptibility to the glutamate receptor agonist N-methyl-D-aspartate (NMDA) and the neurotoxin trimethyltin (TMT), as demonstrated by the cellular uptake of propidium iodide (PI), which was used as a reproducible and quantifiable marker for neuronal degeneration. We conclude that organotypic brain slice cultures can grow on silicon-based three-dimensional microelectrode arrays and develop normally with display of normal subfield differentiated susceptibilities to known excito- and neurotoxins. From this it is anticipated that the set-up, designed for recording of electrophysiological parameters, can be used for long-term studies of defined neuronal networks and provide valuable information on both normal, neurotoxicological and neuropathological conditions.

Animals↗
PubMed1986

Peripheral and central nervous system lesions caused by triethyl- and trimethyltin salts in rats.

Both trimethyltin and triethyltin salts are known to produce toxic lesions in the central nervous system. Triethyltin intoxication has been associated with central intramyelin edema, while trimethyltin has been shown to produce neuronal necrosis in selected limbic and sensory regions of the brain. Only scant attention has been paid to peripheral nerves of animals treated with alkyltins. In this study, we have treated rats with 6 or 8 mg/kg trimethyltin, and 1, 2, 4, 6, or 8 mg/kg triethyltin (single or multiple exposure), and evaluated in detail at the light microscope level both central and peripheral nervous system lesions. In addition to the central neuron necrosis or myelin edema described previously, both compounds produced peripheral axon degeneration and chromatolysis of large spinal cord and brain stem neurons. Chromatolysis was seen in reticular neurons of the brain stem and ventral horn or spinal cord in rats receiving high doses (6 or 8 mg/kg) of triethyltin, and in these same areas plus mesencephalic trigeminal nucleus in animals treated with trimethyltin. Wallerian-like degeneration of peripheral axons was seen in sciatic and tibial nerve and ventral roots of animals receiving 3 injections of 4 mg/kg or single or multiple injections of 6 or 8 mg/kg triethyltin. Axon degeneration was also seen in sciatic and tibial nerves 21 days after a single exposure to 8 mg/kg trimethyltin. Since myelin edema is believed to be reversible, the axonal changes described here may be of greater clinical significance in relation to human exposure.

Animals↗
PubMed2005

Elevated Ca2+(i) transients induced by trimethyltin chloride in HeLa cells: types and levels of response.

Humans are exposed to organotins, like trimethyltin (TMT) chloride via air, water and food, and intoxication might result in severe health complications. Toxic effects of organotin compounds are well documented, but possible mechanisms remain unclear and only little information is available how organometallic species interact with calcium controlling mechanisms. Therefore, the aim of this work was to investigate the effects of TMT on calcium homeostasis in HeLa S3 cells. Dynamic changes of cytosolic calcium (Ca2+(i)) were monitored using laser-scanning microscopy and fluo-4 loaded cells. Application of TMT resulted in sustained as well as in transient elevations of Ca2+(i). The number of reacting cells was directly correlated to the concentration of TMT used: with 500 microM TMT all cells reacted, with 50 microM TMT 80% and with 5 microM 74%. The fast Ca2+(i)-transients (spikes), measured in single cells, occurred even with 0.25 microM TMT and varied in size and duration. The sustained increase of Ca2+(i), measured as the average over all cells, was dose dependent with an approximately 8% increase for 5 microM TMT, approximately 12.3% for 50 microM and approximately 145% for 500 microM TMT. Moreover, this effect was partly reversible. A second application resulted in a similar sustained rise of Ca2+(i) compared to the first application of TMT, there was also no difference when no calcium was added to the external solution (151+/-10% compared to 145+/-15%; 500 microM TMT). This rise of Ca2+(i) was highly reduced (<10% increase) when the internal calcium stores were depleted before TMT (500 microM) was applied. Our data suggest that TMT influences Ca2+(i)-homeostasis of HeLa S3 cells, which might be related to its toxicity in this cell line.

Aniline Compounds↗
PubMed1992

Trimethyltin alters membrane properties of CA1 hippocampal neurons.

Trimethyltin produces pathological changes in the hippocampus, but the physiological mechanisms underlying its toxicity remain unclear. Intracellular recordings of CA1 neurons in rat hippocampal slices were conducted during bath application of 50 and 100 microM trimethyltin and 50 and 200 microM dimethyltin. Trimethyltin slowly depolarized the membrane potential without spontaneous spiking, and decreased input resistance and time constant. Trimethyltin decreased, in a dose-dependent manner, both the elicited action potential and the orthodromically-stimulated action potential amplitudes; increased the threshold current for both elicited and orthodromically-stimulated action potentials; and prolonged the duration of the orthodromic excitatory post-synaptic potential. These trimethyltin-induced effects were not readily reversed. On the other hand, dimethyltin at high concentrations only reduced the amplitude of the orthodromic action potential. Slice viability was compromised following exposure to trimethyltin, but not following dimethyltin. These data demonstrate that decreased membrane time constant and input resistance is an early and reliable indicator of the onset of trimethyltin-induced changes. The effects do not resemble those produced by excitotoxins, but rather share similarities with responses observed during slice hypoxia.

Action Potentials↗
PubMed1999

The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (sigma) receptor ligands involves both sigma1 and sigma2 sites.

1. Sigma (sigma) receptor ligands were previously reported to alleviate learning and memory impairments on several pharmacological and pathological rodent models of amnesia. Such effect was demonstrated as involving the sigma1 subtype of sigma receptor. 2. In this study, we characterized the pharmacological effect mediated by sigma ligands on two lesional models of amnesia in mice: (1) the hypoxia-related learning and memory impairment model induced by repeated exposure to carbon monoxide (CO) gas; and (2) the intoxication with trimethyltin (1 mg kg(-1)). 3. The selective sigma1 ligand PRE-084 (1 mg kg(-1)) or the non-selective sigma1/sigma2 compounds DTG (0.1 mg kg(-1)), BD1008 (3 mg kg(-1)), and haloperidol (0.1 mg kg(-1)) reversed significantly the spontaneous alternation deficits observed 7 days after exposure to CO or 14 days after intoxication with trimethyltin. 4. The selective sigma1 receptor antagonist NE-100 (1 mg kg(-1)) was ineffective by itself, but blocked completely the PRE-084 effects, partially the DTG effects, and did not affect the effects induced by BD1008 or haloperidol. 5. A similar pharmacological profile was observed in the step-down type passive avoidance test performed 8 days after exposure to CO. 6. These results show that, in contrast to the previously reported amnesia models, the impairments induced after exposure to CO or intoxication with trimethyltin could be alleviated not only by sigma1 receptor agonists but also by sigma2 agonists. The particular pattern of neurodegeneration observed in these lesional models may explain these differences.

Amnesia↗
PubMed1992

Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity.

Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, and hydroxyl radicals are believed to be initiators of peroxidative cell damage. This paper focused on the use of 2',7'-dichlorofluorescein-diacetate (DCFH-DA) to quantitate cerebral ROS as an index for neurotoxicity. This technique employs an assay of dichlorofluorescein (DCF), the fluorescent product of dichlorofluorescein (DCFH). Data from studies using various free radical generating systems, several iron chelators and hydroxyl radical scavengers suggest that DCFH oxidation may result in several reactive intermediates. In a biological system (synaptosomes isolated from untreated rats) DCF fluorescence was stimulated by ascorbate or FeSO4, while deferoxamine inhibited the ascorbate/FeSO4-induced stimulation of DCF formation. Two organometals, methylmercury (MeHg) and trimethyltin (TMT), known to produce neurotoxicity were tested. In vitro exposure to MeHg (10-20 microM) increased the rate of formation of ROS while TMT (5-40 microM) had no effect. In vivo, 48 hr and 1 week after a single injection of MeHg (1 mg/kg, i.p.) in mice and 1 week after a single injection of MeHg (5 mg/kg, i.p.) in rats, the rate of formation of ROS in both rat and mouse cerebellum was significantly increased. Pretreatment with deferoxamine, a potent iron-chelator, prevented MeHg-induced increase of ROS. In hippocampus and frontal cortex, ROS formation rates were also elevated 48 hr after TMT injection (3 mg/kg, i.p.) in mice. These results demonstrate that DCF fluorescence provides a good measure of overall ROS formation in synaptosomes of both in vitro as well as in vivo systems. Since ROS formation was selectively increased in areas known to be specifically vulnerable to organometals (cerebellum in the case of MeHg and hippocampus in the case of TMT), these studies further support that oxidative damage may be the primary mechanism underlying the neurotoxicity induced by these organometals.

Animals↗
PubMed1992

Effects of trimethyltin on repeated acquisition (learning) in the radial-arm maze.

Trimethyltin (TMT) was used as a positive control neurotoxicant to evaluate a repeated acquisition procedure for the 8-arm radial maze. Ten male Long-Evans rats were trained to collect a single food pellet at the end of each baited arm on each trial of a daily 12-trial test session. Four of the eight arms were baited on all trials of a given session. The set of four baited arms was changed each day: thus the rats were required to learn a new set of baited arms in each session. In trained rats, error frequencies (entries into unbaited arms) declined from about 4 on Trial 1 to less than 1 on Trials 4-12 in each session: this within-session error reduction thus defined an acquisition baseline which was evaluated for its sensitivity to TMT. Learning was impaired after 7 mg/kg (iv) TMT, as shown by a slower decline in within-session error frequencies in all treated rats. Errors and response times were elevated for 5 weeks after TMT but returned to control levels thereafter. Histological examination of hippocampi showed damage in all treated rats 18 weeks after treatment; however, no significant relationship between degree of damage and behavioral effect was observed. Analysis of errors showed that TMT more strongly impaired the rats' ability to avoid arms in the current unbaited set than those baited arms already entered on a given trial (i.e., working memory). These dissociations between behavior and hippocampal morphology in terms of time course, magnitude of effect across animals, and error type suggest that performance of this task does not depend upon hippocampal integrity, as do other tasks involving spatial working memory. Recovery of function in this kind of task may shed light on processes of neural plasticity after exposure to neurotoxic compounds.

Animals↗
PubMed2005

Apoptosis of cerebellar granule cells induced by organotin compounds found in drinking water: involvement of MAP kinases.

Mono- and dialkyl organotin compounds are used primarily as heat stabilizers in polyvinyl chloride (PVC) plastics. Recently, monomethyltin (MMT), dimethyltin (DMT), monobutyltin (MBT), and dibutyltin (DBT) have been detected in water from homes and businesses served by PVC pipes. While trialkyl organotins such as trimethyltin (TMT) and triethyltin (TET) are well known neurotoxicants, the toxicity of the mono- and dialkyl organotins is not well described. The present study compared the cytotoxicity of organotins found in drinking water with the known neurotoxicant TMT in primary cultures of cerebellar granule cells, and examined the role of MAP kinase signaling in organotin-induced cell death. Twenty-four hour exposure to TMT resulted in a concentration-dependent decrease in cell viability with an EC(50) of 3 microM. Exposure to MMT, DMT, and MBT at concentrations up to 10 microM had no effect. DBT, however, was very potent, and decreased cell viability with an EC(50) of 0.3 microM. Staining of organotin-treated cerebellar granule cells with the nuclear dye Syto-13 revealed that TMT and DBT, but not MMT, DMT, or MBT, produced condensation and fragmentation of chromatin characteristic of apoptosis. TMT- and DBT-induced apoptosis was confirmed using TUNEL staining and measurement of PARP cleavage. Activation of MAP kinase pathways was examined after 6 h of exposure to the organotins which induced apoptosis. Both TMT and DBT activated ERK1/2, but only TMT activated the JNK/c-Jun and p38 pathways. Pharmacologic blockade of JNK/c-Jun and p38 activation significantly decreased apoptosis produced by TMT, but not by DBT. These results show that DBT is a potent neurotoxicant in vitro, but unlike TMT, does not induce cell death via activation of MAP kinase signaling.

Animals↗
PubMedDate not supplied

Morphometric analysis of the developing rat brain.

In 2 studies, a method of linear morphometry was applied to regulatory developmental neurotoxicity studies in the rat. The first study involved the development of the brain during postnatal days (PNDs) 7-63, and the second involved the effects of 8 mg/kg i.p. trimethyltin chloride (TMT) to rats at PND 8, with morphometry performed at PNDs 12 and 24. The results of the TMT linear morphometry were compared with those from stereologic counting of neurons in the cerebral cortex, piriform cortex, and hippocampus. Stereology produces more meaningful data than simple linear morphometry for use in the regulatory assessment of the developmental neurotoxicity potential of compounds.

Aging↗
PubMed1993

Effects of methylmercury and trimethyltin on cardiac, platelet, and aorta eicosanoid biosynthesis and platelet serotonin release.

The effects of two organometals on heart, platelet, and aorta prostaglandin biosynthesis were examined in vitro. Methylmercuric chloride (MMC, 39-796 nM) increased the biosynthesis of thromboxane A2 (TxA2) and prostacyclin (PGI2) in the heart and stimulated the biosynthesis of PGI2 in incubates of aorta rings. The aorta biosynthesis of PGI2 was monitored by its inhibition of platelet aggregation and serotonin [5-hydroxytryptamine (5-HT)] secretion, while the metabolites 6-keto-PGF1a and TxB2 were quantified by radioimmunoassay. In platelet experiments, low concentrations of MMC (5 microM) enhanced aggregation to adenosine diphosphate (ADP) and at high concentrations MMC (50-100 microM) directly stimulated aggregation and 5-HT secretion. These effects of MMC were inhibited by nonsteroidal antiinflammatory drug, thromboxane synthetase, and phospholipase A2 inhibitors. Trimethyltin (TMT), another highly toxic organometal, had no effect on prostaglandin biosynthesis in either heart or aorta incubates. TMT did not increase platelet aggregation responses to ADP, nor did it directly trigger aggregation. At moderate concentrations, TMT (20-45 microM) slightly depressed ADP aggregation; however, this was paradoxically associated with increased 5-HT secretion. In platelets pretreated with either NDGA or ASA, TMT in the absence of aggregation enhanced 5-HT secretion in response to ADP. TMT, unlike MMC, did not stimulate platelet TxB2 biosynthesis from exogenous [3H]arachidonic acid, whereas MMC stimulates heart, vascular, and platelet eicosanoid biosynthesis. TMT, unlike MMC, does not directly activate the arachidonic acid cascade.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Effects of superoxide dismutase and U74389G on acute trimethyltin-induced cochlear dysfunction.

Reactive oxygen species (ROS) generation has been implicated in the ototoxicity induced by several pharmaceutical agents. The present study examined the efficacy of the ROS scavenger polyethylene glycol-conjugated superoxide dismutase (PEG.SOD), and a 21-aminosteroid (U74389G), in ameliorating the acute cochlear dysfunction induced by the environmental ototoxicant trimethyltin chloride (TMT). Thirty pigmented guinea pigs were divided into six experimental conditions, as defined by preexposure and exposure administrations: saline-saline, PEG.SOD-saline, U74389G-saline, saline-TMT, and U74389G-TMT. Electrophysiological potentials (compound action potential (CAP) and cochlear microphonic (CM) were recorded for 10 acoustic frequencies, and then a preexposure agent (U74389G, 4.5mg/kg; PEG.SOD, 10,000 U/kg; or 0.9% saline) was administered i.v. Thirty minutes later, potentials were retested, and an exposure agent (0.9% saline or TMT, 0.5 mg/kg) was administered i.p. CM and CAP were retested at 30, 60, and 90 min postexposure time points, in order to assess changes in auditory responsiveness. Mean changes in 1.0-microV root mean square CM isopotential values did not differ significantly in any group from those of saline-saline controls. In the saline-TMT group, CAP thresholds increased significantly at all test frequencies relative to those of the saline-saline control group. While mean CAP threshold shifts in the U74389G-TMT group were as great as those in the saline-TMT group, such values in the PEG.SOD-TMT group were significantly lower. These results suggest that ROS formation may be involved in acute TMT-induced CAP disruption, for which PEG.SOD, but not U74389G, provides partial protection.

Action Potentials↗
PubMed1995

Trimethyltin-induced neuropathy in the rat: interaction with thermoregulation.

The enhanced production of glial fibrillary acidic protein (GFAP) by astroglia appears to be a general response of the CNS to many types of toxic insult. The organometallic neurotoxicant, trimethyltin (TMT), is one such agent known to increase the production of GFAP as a consequence of widespread neuronal destruction. TMT also leads to transient reductions in body temperature (Tb), a response which may alter the neurotoxic effects of this compound. To study the role of Tb in the neurotoxic effects of TMT, rats were injected (i.v.) with saline or 8.0 mg/kg TMT and maintained at ambient temperatures (Ta) of 16, 22, or 30 degrees C for 72 hr while Tb (core) was measured periodically. Animals were then housed at a Ta of 22 degrees C for 35 days after which time their brains were removed and dissected into hippocampus, cerebral cortex, striatum, midbrain and cerebellum for subsequent analysis of GFAP. TMT led to a significant decrease in Tb of rats housed at 22 degrees C measured 3 hr after treatment. Tb of rats maintained at Ta's of 16 and 30 degrees C was unaffected by TMT initially (i.e., no hypothermia); however, by 72 hr after TMT, rats maintained at 22 and 30 degrees C had a significantly elevated Tb. TMT led to marked elevations in GFAP levels, a response that was affected by Ta. In the hippocampus the elevation in GFAP was significantly greater in rats housed at 16 and 30 degrees C. A similar pattern was seen in the midbrain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Trimethyltin disrupts loudness recruitment and auditory threshold sensitivity in guinea pigs.

Trimethyltin (TMT) impairs auditory thresholds within minutes of systemic administration. However, there are no data which relate to the output of the auditory nerve at sound levels above threshold. In this experiment, we evaluated the functional effects of TMT on the auditory threshold by identifying the sound level which just produced a detectable compound action potential (CAP). We also assessed outer hair cell function by measuring the cochlear microphonic (CM), a nonpropagated ac potential which is phase-locked to the stimulus. Finally, we measured the growth of the N1 amplitude as a function of stimulus intensity at levels above threshold and of the summating potential (SP), a dc potential which has multiple generators. To isolate cochlear from systemic effects of TMT, the agent was applied directly to the round window, a structure separating the middle and inner ear, of anaesthetized guinea pigs. We show that TMT applied to the round window membrane can disrupt the function of the cochlea. Measurements of auditory function at supra-threshold levels showed clearly that TMT reduced the amplitude of N1 while having no measurable effect on the SP. These findings indicate that TMT blocks the recruitment of neuronal elements by loud sound. This pattern of impairment differs from that observed with aminoglycoside antibiotics, hypothermia, and presbycusis in which loudness recruitment has been reported.

Action Potentials↗
PubMedDate not supplied

Attenuation of trimethyltin-evoked glutamate (GLU) efflux from rat cortical and hippocampal slices.

Trimethyltin (TMT) is a toxic alkyltin that produces neuronal necrosis in the CNS. TMT stimulates the efflux of the excitatory amino acid glutamate (GLU) from rat cortical slices. This release is concentration dependent, partially calcium dependent, but not inhibited by calcium channel blockers or a NMDA antagonist. In the present study the compounds furosemide, bumetanide, 4,4'-diisothiocy-anatostilbene-2,2'-disulfonic acid (DIDS), and DL-threo-beta-hydroxyaspartic acid (HAA) were tested for their ability to attenuate TMT-stimulated GLU efflux from rat cortical and hippocampal slices. Furosemide (1 mM) reduced the TMT-induced GLU efflux in cortical slices and hippocampal slices, but bumetanide (0.1 mM) had no effect on TMT-induced GLU efflux. DIDS (1 mM) demonstrated a trend toward decreasing GLU efflux from TMT stimulation in both the cortex and hippocampus, but this reduction was not significant. However, DIDS was able to prevent the decrease in intracellular GLU content produced by TMT in both the cortical and hippocampal slices. HAA (1 mM) increased the net GLU efflux in both cortical slices and hippocampal slices, and produced a significant depletion of the glutamate content of the slices. Taurine efflux was stimulated by TMT treatment but was not blocked by the chloride transport inhibitors. These data suggest that cell swelling-induced release of GLU may not be directly involved in TMT-induced GLU efflux, and that TMT does not appear to elicit GLU efflux by a mechanism involving reversal of the GLU transporter.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗