Biomedical subjects

S Barone

Publications and source records attributed to S Barone.

At least 37 records · Page 2Linked to original sources

PubMed1998

Gestational exposure to chlorpyrifos: apparent protection of the fetus?

Previous studies have shown that, in general, young, postnatal animals are more sensitive than adults to the toxic effects of anticholinesterase (antiChE) pesticides. Paradoxically, often fetal brain cholinesterase (ChE) is less inhibited than maternal brain after gestational exposure to an antiChE, presumably due to placental and fetal detoxification of the antiChE. The present investigation was designed to study selected toxicokinetic and toxicodynamic factors surrounding the toxicity of chlorpyrifos (CPF; [O,O'-diethyl O-3,5,6-trichloro-2-pyridyl] phosphorothionate) in pregnant rats dosed repeatedly or singly during late gestation. Dams were dosed daily (po) with CPF in corn oil (0 or 7 mg/kg) on gestational days (GD) 14 to 18. Animals were euthanized at 2 to 120 h after the last dose and tissues were collected for enzyme analysis. Using this dosing regimen, we found that (1) the time of maximal ChE inhibition was the same (i.e., 5-10 h after dosing) for both maternal and fetal brain, (2) the degree of fetal brain ChE inhibition was 4.7 times less than maternal brain inhibition, and (3) the detoxification potential (i.e., carboxylesterase and chlorpyrifos-oxonase) of the fetal tissues was very low compared to the maternal tissues. A separate group of experiments showed that if pregnant dams received only one oral dose of 7 or 10 mg/kg CPF on GD18, the degree of ChE inhibition in the fetal brain was comparable to the maternal brain ChE inhibition. Taking into consideration the net increase (more than fourfold) in fetal brain ChE activity from GD14 to 18 in control animals, and the fact that maternal brain ChE was inhibited more than fetal brain ChE only in a repeated-dosing regimen, we conclude that the fetus is not genuinely protected from the toxic effects of a given dose of CPF. We propose that fetal brain ChE is simply able to recover more fully between each dose as compared to maternal brain ChE, giving the illusion that the fetal compartment is less affected than the maternal compartment.

Animals↗

PubMed1998

Repeated exposure of adult rats to Aroclor 1254 causes brain region-specific changes in intracellular Ca2+ buffering and protein kinase C activity in the absence of changes in tyrosine hydroxylase.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants, some of which may be neurotoxic. In vitro studies from this laboratory indicated that noncoplanar PCBs perturbed intracellular signal transduction mechanisms including Ca2+ homeostasis, receptor-mediated inositol phosphate production, and translocation of protein kinase C (PKC). In the present study, we examined the effects of PCBs in vivo by dosing adult male Long-Evans rats orally with Aroclor 1254 (0, 10, or 30 mg/kg/day; 5 days/week for 4 weeks) in corn oil. At 24 h after the last dose, rats were tested for motor activity in a photocell device for 30 min. Immediately, the rats were euthanized, blood was collected for thyroid hormone analysis, and brains were removed, dissected into regions (cerebellum, frontal cortex, and striatum), and subcellular fractions were obtained for neurochemical analysis. Following Aroclor 1254 treatment, body weight gain in the high-dose group was significantly lower than the control and low-dose groups. Horizontal motor activity was significantly lower in rats dosed with 30 mg/kg Aroclor 1254. Ca2+ buffering by microsomes was significantly lower in all three brain regions from the 30 mg/kg group. In the same dose group, mitochondrial Ca2+ buffering was affected in cerebellum but not in cortex or striatum. Similarly, total cerebellar PKC activity was decreased significantly while membrane-bound PKC activity was significantly elevated at 10 and 30 mg/kg. PKC activity was not altered either in cortex or the striatum. Neurotransmitter levels in striatum or cortex were slightly altered in PCB-exposed rats compared to controls. Furthermore, repeated oral administration of Aroclor 1254 to rats did not significantly alter forebrain tyrosine hydroxylase immunoreactivity or enzymatic activity. Circulating T4 (total and free) concentrations were severely depressed at both doses in Aroclor 1254-exposed rats compared to control rats, suggesting a severe hypothyroid state. These results indicate that (1) in vivo exposure to a PCB mixture can produce changes in second messenger systems that are similar to those observed after in vitro exposure of neuronal cell cultures; (2) second messenger systems seem to be more sensitive than alterations in neurotransmitter levels or tyrosine hydroxylase involved in dopamine synthesis during repeated exposure to PCBs; and (3) the observed motor activity changes were independent of changes in striatal dopamine levels.

Animals↗

PubMed1997

Damage to the NBM leads to a sustained lesion-induced increase in functional NGF in the cortex.

Bilateral infusions of colchicine or vehicle were made in the nucleus basalis magnocellularis of rats. Cortical homogenates were assessed in a choline acetyltransferase (ChAT) activity assay and a PC12 cell neurite outgrowth assay 3, 7, 14, 28, 35 or 84 days post-lesion. Cortical ChAT activity was initially decreased by 30%, followed by recovery to control levels at 84 days post-lesion. Cortical nerve growth factor (NGF) activity was increased 35% above control levels at all time points following colchicine infusion, while addition of a NGF antibody blocking all activity. The data show an increase in functional NGF in the target area of the lesioned neurons preceding and coinciding with regional recovery of a cholinergic marker, suggesting that NGF has a role in the cholinergic recovery.

Animals↗

PubMed1997

Suppressed formation of bone marrow adherent layers derived from acute myeloid leukemia patients after in vitro exposure to interleukin-4.

Long-term bone marrow cultures from ten acute myeloid leukemia (AML) patients exposed to recombinant human (rhu) interleukin (IL) 4 from culture initiation failed to develop adherent layers at 5 weeks as compared to controls. The adherent layers from two of our patients expressed IL-1 beta transcripts constitutively, and all produced IL-6 and leukemia inhibitory factor (LIF) proteins. Our results demonstrate that rhuIL-4 markedly inhibited AML-derived adherent layer formation in a time- and dose-dependent manner, and this effect was not mediated through enhanced apoptosis and did not correlate with IL-1 beta, IL-6 or LIF production.

Acute Disease↗

PubMed1995

Disruption of cerebellar maturation by an antimitotic agent impairs the ontogeny of eyeblink conditioning in rats.

This study represents an attempt to establish a relationship between maturation of the cerebellum and the ontogeny of eyeblink conditioning in the rat. Experiments 1 and 2 examined the effects of disrupting cerebellar maturation by neonatal exposure to the antimitotic agent methylazoxymethanol (MAM) on the ontogeny of eyeblink conditioning in infant rats. Experiment 1 demonstrated that neonatal exposure to MAM on Postnatal Day 4 (PND4) and 7 severely disrupted cerebellar maturation. This effect appeared to be specific in that there was no overt dysmorphology in other brain regions. MAM treatment also severely disrupted associative eyeblink conditioning in rats given training on PND24 and 25. However, exposure to MAM had no effect on the unconditioned response, T-maze delayed alternation, or conditioned suppression of ongoing behavior. In Experiment 2, MAM was given on PND4 and 7 and pups were tested behaviorally on PND17-18, 20-21, or 31-32. Cerebellar hypoplasia was most dramatic shortly after exposure. The cerebellar cortex continued to mature after exposure to MAM, but development of morphological endpoints examined here were static from PND19 to 33. Eyeblink conditioning was impaired at all ages, indicating that there was no functional recovery following neonatal exposure to MAM over the age range tested. These experiments suggest that normal cerebellar maturation may be important for the ontogeny of eyeblink conditioning.

Animals↗

PubMed1995

Effects of 3,3'-iminodipropionitrile on the peripheral structures of the rat visual system.

Adult male Long-Evans rats received 3,3'-iminodipropionitrile (IDPN; 400 mg/kg i.p.) and were killed one day after one dose, or one, three, seven, thirty-five, or seventy day(s) following 3 consecutive daily doses for histological analysis of the eye. Histological alterations in visual structures were not observed before one day after the third dose of IDPN. Somato-dendritic swelling of cells in the inner nuclear (IN) layer was seen prior to retinal detachment (1 day after cessation of dosing) followed by progressive retinal degeneration (35 and 70 days). IDPN exposure resulted in opacification of the cornea and vascular hemorrhaging into the subretinal space (3 days) followed by complete detachment of the retina (7 days). The corneal opacification was transient and resolved by 14 days post-treatment. The retina underwent complete spontaneous reattachment between 35 and 70 days after IDPN administration. A subsequent experiment was performed to characterize the dose-response of IDPN on retinal histology, 2 weeks after the last dose (0, 100, 200, 400 mg/kg x 3 days). In the dose-response experiment, retinal detachment and degeneration in the IN layer were only apparent in the 400 mg/kg dose group. However, increased GFAP immunoreactivity in the retina was observed in the 200 mg/kg dose group without overt retinal pathology. Results indicate that the corneal opacification, vascular hemorrhaging, and detached retinae recovered in a time-dependant manner, while neurodegeneration of the visual retina was progressive, even after the retina had reattached. The present study indicates that this toxicant may have direct effects on both neural and non-neural structures, and characterizes the time-course and dose-response of histopathological changes in the retina.

Animals↗

PubMed1994

Comparison of intracranial infusions of colchicine and ibotenic acid as models of neurodegeneration in the basal forebrain.

Colchicine and ibotenic acid were compared for their ability to produce neurodegeneration and cognitive deficit after bilateral infusions into the nucleus basalis magnocellularis of male Long-Evans rats. Four weeks post-lesion, there was no difference in locomotor activity following infusion of either neurotoxicant or vehicle. In a passive avoidance task, both treated groups had significantly shorter step-through latencies compared with vehicle. Five weeks post-lesion, rats were killed for neurochemistry or histochemistry. Choline acetyltransferase (ChAT) activity in both the frontal and parietal cortex was significantly decreased (25-35%) in the colchicine- and ibotenic acid-infused rats when compared to control. There was no effect of either neurotoxicant on ChAT activity in the hippocampus or striatum. Both neurotoxicants produced damage in the general area of the ventromedial pallidum, although ibotenic acid infusion consistently produced a larger area of damage as assessed in Nissl-stained sections. Analysis of the number of ChAT-immunoreactive cells in the nucleus basalis magnocellularis (NBM) showed an average 60% cell loss following colchicine infusion and a 75% cell loss after ibotenic acid infusion. Area of glutamic acid decarboxylase (GAD) staining was significantly decreased in several regions surrounding the NBM for ibotenic acid (51% average decrease), and showed non-significant decreases (28%) following colchicine infusion. Colchicine infusion decreased dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; ibotenic acid had no effect on brain catechol of indoleamine levels. The results indicate that although similar cholinergic hypofunction and behavioral deficits were achieved, several non-cholinergic differences between the neurotoxicants were detected.

Animals↗

PubMed1994

Cognitive and neuroanatomical effects of triethyltin in developing rats: role of age of exposure.

Long-Evans rat pups were injected i.p. on postnatal day 5 (PND5) or 12 with 0, 3, or 5 mg/kg triethyltin sulfate (TET) and then tested on T-maze delayed alternation on PND21 or 28. Delayed alternation learning was impaired on PND21 and 28 in pups given 5 mg/kg TET. Pups given 5 mg/kg TET on PND5 were more impaired on delayed alternation than pups given 5 mg/kg TET on PND12. Pups given 3 mg/kg TET on PND5 or 12 were unimpaired at either age of testing. On the day following training, pups were sacrificed for histological assessment employing Nissl- or immunohistochemical staining for glial fibrillary acidic protein (GFAP), a putative marker of gliosis. Pups given 5 mg/kg TET on PND5 showed increases in GFAP immunoreactivity (IR) in subiculum, amygdala, hippocampus, piriform cortex, and entorhinal cortex with concomitant decreases in Nissl-stained cells in these regions. Pups given 5 mg/kg TET on PND12 showed increases in GFAP IR in piriform cortex, amygdala and dorsal hippocampus with concomitant decreases in Nissl-stained cells in these regions. Exposure to 3 mg/kg TET on PND5 and PND12 produced a mild increase in GFAP IR in piriform cortex and amygdala but no discernible loss of Nissl-staining in these respective regions. TET-induced behavioral deficits appear related to damage of structural correlates of the human temporal lobe and not piriform cortical pathology. These results demonstrate that the day of exposure greatly influences the magnitude of the cognitive deficits and neuropathology associated with exposure to TET. There appears to be a critical period during postnatal development for the developmental neurotoxicity of this compound.

Animals↗

PubMed1994

Progressive changes in striatal dopaminergic markers, nigral volume, and rotational behavior following iron infusion into the rat substantia nigra.

Excess iron (Fe) within the substantia nigra zona compacta (SNc) has been implicated in the pathogenesis of Parkinson's disease (PD). We recently reported that intranigral Fe infusion into the rat substantia nigra (SN) induces dose-dependent SN neurodegeneration and associated reductions in striatal dopaminergic (DA) markers. The objective of the present study was to determine whether infused Fe is capable of inducing persistent/progressive neurodegenerative changes relevant to PD. Following unilateral infusions of vehicle, 1.25 or 2.10 nmol Fe into the rat SN, SNc neuronal loss, SN volume, striatal neurochemical markers, and apomorphine-induced rotational behavior were assessed at 2, 4, and 6 months. Semiquantitative analysis of thionine-stained SNc neurons demonstrated an initial modest neuronal loss which remained stable through 6 months postinfusion. Fe-induced SN atrophy was dose-dependent and progressive through 6 months. Striatal DA and homovanillic acid levels were progressively decreased at least through 4 months following 1.25 nmol Fe infusion; both doses of Fe induced significant reductions of both DA markers at 4 months with no recovery evident through 6 months. Apomorphine-induced rotational behavior progressively increased for both Fe infusion groups through the 6 months of testing. These data indicate that a single exposure of the SN to a modest amount of Fe can induce persistent/progressive changes occurring through a number of months postinfusion and further establishes intranigral Fe infusion as an animal model for PD.

Animals↗

PubMed1994

Developmental neurotoxicity: evaluation of testing procedures with methylazoxymethanol and methylmercury.

Testing procedures for identification of potential developmental neurotoxicants were evaluated using two prototypical developmental neurotoxicants, methylazoxymethanol (MAM) and methylmercury (MeHg). Evaluation of offspring of Long-Evans rats incorporated assessments of developmental toxicity, neurochemistry, histology, and behavior, with most testing being completed near weaning. A number of endpoints in the testing strategy were sensitive to the effects of prenatal exposure to MAM [30 mg/kg on Gestation Day (GD) 15]: (1) MAM caused reduced neonatal body weights but did not effect viability or postnatal survivorship; (2) measurement of total and regional brain weight and histological analysis showed that a number of regions, the cortex and hippocampus in particular, were affected by MAM exposure; (3) an assay for glial fibrillary acidic protein (GFAP) showed that the concentration of this protein was significantly increased in the cortex and hippocampus of treated offspring; (4) a T-maze delayed-alternation procedure indicated that MAM-treated pups were slower in the acquisition phase of the task relative to control pups; (5) motor activity testing revealed hyperactivity in treated offspring that persisted into adulthood; and (6) acoustic startle procedures revealed reduced startle amplitudes in preweanlings. Few endpoints were significantly affected by prenatal MeHg exposure (1, 2, or 4 mg/kg on GD 6-15). High fetal and neonatal mortality and lower neonatal body weights were detected at the highest dose of MeHg. Although minimal effects of MeHg may reflect a relative insensitivity of the test species and/or the test methods, the combined results from both chemicals suggest that some procedures not currently required in the developmental neurotoxicity guideline may be useful in hazard identification, and further evaluation with other chemicals, species, strains, and/or exposure paradigms may be warranted.

Alkylating Agents↗

PubMed1994

Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina.

Several reports have suggested that exposure to organophosphate pesticides damages the visual system. The prolonged effects of an acute dose of fenthion (dimethyl 3-methyl-4-methylthiophenyl phosphorothionate) were studied on the cholinergic system of the rat retina. Fenthion was administered in a single dose of 0 or 100 mg/kg (sc, in corn oil) to adult, male, Long-Evans rats. The animals were killed 4, 14, or 56 days after treatment and cholinesterase (ChE) activity as well as muscarinic receptor (mChR) function measured in the retina and frontal cortex. Fenthion produced 89% inhibition of ChE activity in both tissues at 4 days, and, although there was recovery, slight (15%) inhibition of the enzyme activity was still observed at 56 days in both tissues. A long-lasting decrease in carbachol-stimulated inositolphosphate (IP) release was observed following fenthion treatment in the retina: IP release was depressed at 4 days and this depression persisted up to 56 days after dosing. The density of mChR in the retina as well as in the cortex was decreased by 14-20% at 4 days and returned to control levels by 56 days. Fenthion had no effect on the metabolism of phospholipids in the retina following intraocular injections of labeled precursors [3H]myo-inositol, [methyl-14C]choline, or [2-3H]glycerol 4 days after fenthion treatment. These prolonged effects of fenthion on mChR function (signal transduction) appear to be specific to the retina as the cortex showed no change in receptor-stimulated IP release even in the presence of significant mChR down-regulation and ChE inhibition. This dose of fenthion did not produce overt morphological changes in the retina or in the cortex, as observed with light microscopy, although an increase in glial fibrillary acidic protein immunoreactivity (GFAP IR) extending from the internal limiting membrane to the external limiting membrane of the retina was noted. This increase in GFAP IR was observed at 14 days and persisted as long as 56 days post-treatment in the retina, but was not noted in the cortex at any of the time points studied. Thus, this long-lasting perturbation in the retinal cholinergic second messenger system induced by fenthion may occur independently of depressed ChE activity and down-regulation of mChR.

Animals↗

PubMed1994

The ototoxicity of 3,3'-iminodipropionitrile: functional and morphological evidence of cochlear damage.

Previous reports have suggested that IDPN may be ototoxic (Wolff et al., 1977; Crofton and Knight, 1991). The purpose of this research was to investigate the ototoxicity of IDPN using behavioral, physiological and morphological approaches. Three groups of adult rats were exposed to IDPN (0-400 mg/kg/day) for three consecutive days. In the first group, at 9-10 weeks post-exposure, thresholds for hearing of 5.3- and 38-kHz filtered clicks were measured electrophysiologically and brainstem auditory evoked responses (BAERs) were also recorded to a suprathreshold broadband click stimulus. A second set of animals was tested at 9 weeks for behavioral hearing thresholds (0.5- to 40-kHz tones) and at 11-12 weeks post-exposure for BAER thresholds (5- to 80-kHz filtered clicks). A third group of animals was exposed (as above), and killed at 12-14 weeks post-exposure for histological assessment. Kanamycin sulfate was used as a positive control for high-frequency selective hearing loss. Surface preparations of the organ of Corti were prepared in order to assess hair cells, and mid-modiolar sections of the cochlea were used to examine Rosenthal's canal and the stria vascularis. Functional data demonstrate a broad-spectrum hearing loss ranging from 0.5 kHz (30 dB deficit) to 80 kHz (40 dB deficit), as compared to a hearing deficit in kanamycin-exposed animals that was only apparent at frequencies greater than 5 kHz. Surface preparations revealed IDPN-induced hair cell loss in all turns of the organ of Corti, with a basal-to-apical gradient (more damage in the basal turns) at the lower dosages. At higher dosages there was complete destruction of the organ of Corti. There was also a dosage-related loss of spiral ganglion cells in all turns of the cochlea, again with a basal-to-apical gradient at the lower dosages. These data demonstrate that IDPN exposure in the rat results in extensive hearing loss and loss of neural structures in the cochlea.

Acoustic Stimulation↗

PubMed1994

Compensatory changes in the hippocampus following intradentate infusion of colchicine.

Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits behavioral, neurochemical and neuroanatomical changes. Colchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antagonists and more sensitive to cholinergic agonists. These behavioral changes are associated with time- and dose-dependent alterations in the cholinergic signal transduction mechanism. Carbachol-stimulated turnover of phosphoinositides is increased in the hippocampus of colchicine-treated rats; similar changes are not observed in the cortex or striatum of colchicine-treated animals. Intradentate colchicine produces a significant increase in choline- acetyltransferase activity and staining for acetylcholinesterase activity in the hippocampus, suggesting reactive synaptogenesis of cholinergic fibers. Other studies have shown that the integrity of the septohippocampal pathway is necessary for these colchicine-induced compensatory changes to occur. It is suggested that the mechanism for these neurochemical changes in colchicine-treated animals may be occurring via alterations in negative feedback control of receptor-G-protein-mediated phosphoinositide hydrolysis.

Animals↗

PubMed1993

Developmental differences in neural damage following trimethyl-tin as demonstrated with GFAP immunohistochemistry.

Long-Evans rat pups received intraperitoneal (i.p.) injections of trimethyl-tin (TMT) 6 mg/kg hydroxide or saline on postnatal day (PND) 10 or PND 18 and were sacrificed for immunohistochemical staining for glial fibrillary acidic protein (GFAP) on PND 12, 18, 20, or 25. After dosing with TMT on PND 10 there was a transient increase in GFAP immunoreactivity (IR) in the amygdala, piriform, and entorhinal cortex 2 days post-dosing (PND 12) and a persistent increase in GFAP IR in the hippocampus and cingulate cortex up to two weeks post-dosing. Following dosing with TMT on PND 18 there was a delayed (PND 25) increase in GFAP IR in the amygdala, hippocampus, cingulate, piriform, and entorhinal cortex. In addition, increases in GFAP IR were observed in the neocortex 7 days post-dosing, which was not observed following earlier postnatal dosing. The regions in which gliosis and loss of Nissl-staining were consistent for the different time points of TMT treatment were the amygdala, hippocampus, cingulate, piriform, and entorhinal cortex. The present findings indicate the GFAP immunohistochemistry can be used to reveal regional effects of developmental neurotoxicant exposure during early stages of development.

Animals↗

PubMed1993

The role of the septohippocampal pathway in the mediation of colchicine-induced compensatory changes in the rat hippocampus.

To study the involvement of the septohippocampal pathway in colchicine-induced changes in the hippocampus, colchicine was used to lesion the septum and/or hippocampus of male, Fischer-344 rats. Rats were killed 12 weeks post-lesion and histochemical and biochemical measurements were performed. [3H]-QNB binding, choline acetyltransferase (ChAT) activity and agonist-stimulated release of inositol phosphates (IPs) were measured in hippocampal slices. AChE histochemistry was also performed to visualize AChE positive fibers in the hippocampus. Increases in ChAT activity, AChE staining and carbachol-stimulated IP release observed in hippocampal-lesioned animals were attenuated in animals receiving both septal and hippocampal lesions. However, the decrease observed in [3H]-QNB binding sites after intradentate colchicine was not affected by septal lesions. Subsequent studies also found enhanced sensitivity to excitatory amino acid (EAA)-stimulated IP release in hippocampal-lesioned animals. Similar to the changes observed in carbachol-stimulated PI hydrolysis, this increase was also long-lasting. However, the hyperstimulation of EAA-induced IP release was not attenuated by the septal lesion. Thus, it appears that the neurochemical and morphological changes observed in the hippocampus following intradentate colchicine are dependent upon more than one afferent projection to the hippocampus.

Animals↗

PubMed1992

The neurobiological effects of colchicine: modulation by nerve growth factor.

To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, colchicine (COLCH) or artificial cerebrospinal fluid (ACSF) was infused into the dorsal hippocampus (HPC) followed by unilateral infusion of either purified beta-NGF (in ACSF) or cytochrome C. One week later, animals were tested in activity chambers when NGF treatment was found to reduce the COLCH-induced hyperactivity. Animals were sacrificed 3 or 12 weeks postlesion for neurochemical or morphological analysis. Carbachol-stimulated phosphatidyl inositol (PI) turnover performed in hippocampal slices was not affected by any treatment at 3 weeks. However, 12 weeks after the lesion, CARB stimulation of PI hydrolysis was increased in the COLCH/ACSF group. NGF treatment significantly reduced the hyperstimulation in COLCH-treated rats. Morphological analysis showed that COLCH treatment increased AChE staining in the hippocampus, whereas NGF treatment had no effect on AChE staining. There was no difference in the number of septal ChAT immunoreactive cell bodies of controls or colchicine-treated rats at either time point examined. However, NGF treatment resulted in a significant increase in the number of ChAT immunoreactive cell bodies 3 weeks postlesion. Results from this study indicate that NGF can modify colchicine-induced compensatory changes in hippocampal signal transduction and has transitory influences on cholinergic cells in the medial septum.

Acetylcholinesterase↗

PubMed1991

The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine.

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.

Animals↗

PubMed1991

Long-term changes in phosphoinositide hydrolysis following colchicine lesions of the nucleus basalis magnocellularis.

The effect of bilateral colchicine lesions of the nucleus basalis magnocellularis (NBM) on agonist-stimulated phosphoinositide (PI) hydrolysis was examined in cortical slices 1, 3, or 14 months after surgery. Colchicine lesions resulted in a loss of acetylcholinesterase staining in the cortex which recovered to control levels by 14 months. Choline acetyltransferase activity in the cortex was decreased by 43% one month after lesioning, but returned to control levels by 3 months. In vitro stimulation with carbachol produced a concentration-dependent increase in PI hydrolysis, which was enhanced 3 and 14 months after NBM lesions. Norepinephrine and quisqualate-stimulated PI hydrolysis was also enhanced 14 months after NBM lesions. These results suggest a slow up-regulation of postsynaptic receptor function following presynaptic loss of transmitter.

Acetylcholinesterase↗