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PubMed1996

Rat models of autosomal dominant polycystic kidney disease.

Several rat models of polycystic kidney disease (PKD) have been published. The only rat model of autosomal dominant polycystic kidney disease currently used is the so-called Hannover rat (Han:SPRD cy/+). This model is characterized by a slow progression of uraemia, proteinuria and hyperlipidaemia. Histological changes clearly resemble those seen is human PKD. The localization of Na+/K(+)-ATPase correlating with the phenotype of the cysts--basal in moderately expanded and apical in highly expanded cysts--suggests that the mislocation of the Na+/K(+)-ATPase is involved in the mechanism of cyst expansion rather than formation, and a consequence of cell dedifferentiation rather than an initial event. Of note is a considerable gender difference in disease severity. Disease anticipation or genetic imprinting does not occur. In addition to gender, a number of interventions influence the progression rate: acceleration is noted after unilateral nephrectomy, the induction of acidosis, chloride feeding or an increased protein intake; slowing down of the course occurs after the induction of alkalosis and castration, and after treatment with lovastatin and methylprednisolone. Thus the Han:SPRD cy/+ rat represents the only well-documented rat model of autosomal dominant PKD resembling a number of features of the human disease.

Animals↗
PubMed2005

Notable sequential alterations in notochord volume during development in the Adriamycin rat model.

BACKGROUND/PURPOSE: The Adriamycin rat model (ARM) is a well-established model of the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association. An important finding in the ARM is that Adriamycin induces abnormal notochord morphology in the region of the foregut. Having recently demonstrated notochord hypertrophy in ARM embryos, the authors designed this study to assess notochord volume sequentially from gestational days 10 to 14 (E10-E14) to test the hypothesis that notochord hypertrophy occurs maximally soon after Adriamycin administration. METHODS: Adriamycin (1.75 mg/kg) was administered intraperitoneally to pregnant rats on E7, E8, and E9. Control animals were given saline. Embryos were recovered at E10, E11, E12, E13, and E14 and embedded in paraffin. Quantitative morphology using the Cavalieri technique was performed on hematoxylin and eosin-stained transverse serial sections to determine total embryo and total notochord volume. RESULTS: The percentage volume of notochord per embryo was significantly increased (P < .05) in Adriamycin-treated embryos at all gestational time frames from E10 to E14 when compared with equivalent controls. This increased volume of notochord was found to be maximal at E11. CONCLUSIONS: These data support the authors' previous finding that Adriamycin induces notochord hypertrophy and suggest that notochord volume is increased relative to embryo volume soon after Adriamycin administration and is maximal on E11. The abnormal increase in notochord volume during the critical phase of development may interfere with organogenesis, resulting in the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association.

Abnormalities, Drug-Induced↗
PubMed2002

[Establishment of a new rat model of intrauterine growth retardation].

OBJECTIVE: To establish intrauterine growth retardation (IUGR) models in rats for study of the etiology, pathology and therapy of this disease. METHOD: Partial ligation of the medial segment of the uterine artery and vein was performed in 10 Sprague-Dawley rats with pregnancy (17 d) to establish IUGR models, and another 9 rats with pregnancy of the same length which did not receive the operation were used as control. On day 21 of pregnancy, the fetuses and placentas in both groups were surgically taken and weighted, and the incidence of IUGR and mortality in the fetus were observed. RESULTS: Significant decrease in the average weight of the fetuses (3.32+/-0.54 g) and placentas (0.38+/-0.05 g) occurred in the ligated group as compared with those of the control group (4.55+/-0.76 g and 0.44+/-0.11 g, P<0.005). An incidence of IUGR as high as 33.33% was resulted in the fetus of ligation group, significantly higher than that in the control group (1.14%, P<0.005), but no significant difference was observed in the mortality between the 2 groups (4.94% vs 3.41%, P>0.05). CONCLUSION: IUGR models can be successfully established in SD rats by partial ligation of the medial segment of the uterine artery and vein.

Animals↗
PubMed2002

The mechanisms of intracranial pressure modulation by epidural blood and other injectates in a postdural puncture rat model.

UNLABELLED: The epidural blood patch is considered effective in treating postdural puncture headache. We have developed a postdural puncture model in rats for quantitative evaluation of the magnitude and duration of changes in cerebrospinal fluid (CSF) pressure in the cisterna magna in response to the administration of epidural blood or other moieties. This model was used to compare the efficacy of various methods of epidural injection for restoring and maintaining CSF pressure for up to 240 min. After lumbar dural puncture, CSF pressure declined 3.6 +/- 0.2 mm Hg. Epidural saline (100 microL) injected at the puncture site initially increased pressure by 7.2 +/- 0.7 mm Hg, but it rapidly (7.8 +/- 0.6 min) returned to postdural puncture baseline. A similar initial increase of CSF pressure was observed with equal volumes of all other epidural injectates, but the duration of pressure increase varied greatly. Hetastarch and dextran 40 produced results similar to saline. Only whole blood or fibrin glue consistently increased CSF pressure for the entire 240-min observation period. Whole blood mixed with anticoagulant or injected 20-mm cephalad to the puncture site did not sustain pressure. After laminectomy, direct application of blood or adhesive to the dural defect caused no pressure increase. Continuous infusion of saline after bolus could maintain pressure increase for 180 min, but within 60 min of stopping infusion, pressure returned to baseline. These results confirm the efficacy of the epidural administration of blood or fibrin glue to correct CSF hypotension after dural puncture and also provide insight into the mechanisms of intracranial pressure modulation. Sealing the dural defect does not effectively correct CSF pressure unless an epidural tamponade effect is also maintained. IMPLICATIONS: A rat model was developed to evaluate different drugs that may be injected epidurally to treat postdural puncture headache. Epidural injection of blood or fibrin glue was the most effective method of maintaining increased cerebrospinal fluid pressure after dural puncture. Sealing the dural defect does not effectively correct cerebrospinal fluid pressure unless an epidural tamponade effect is maintained.

Animals↗
PubMed2001

Traumatic arteriogenic erectile dysfunction: a rat model.

We developed a rat model of traumatic arteriogenic erectile dysfunction (ED) for the study of vasculogenic ED. Bilateral ligation of the internal iliac artery was performed on 30 three-month old male Sprague-Dawley rats as an experimental group. The control group consisted of 12 rats which underwent dissection of the internal iliac artery without ligation. Before their euthanization at 3 days, 7 days, and 1 month (10 rats in the experimental group and four rats in the control group at each time point), erectile function was assessed by electrostimulation of the cavernous nerves. Penile tissues were collected for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining, trichrome staining, electron microscopy and RT-PCR for transforming growth factor beta (TGF-beta1), insulin like growth factor-I (IGF-I) and fibroblast growth factors (FGF) mRNA expression. Electrostimulation of the cavernous nerves revealed a highly significant declining of the intracavernous pressure after 3 and 7 days. No significant recovery of erectile function was noted at 1 month. Histology showed degeneration of the dorsal nerve fibers in all experimental rats. There was little decrease in the bulk of intracavernous smooth muscle in the experimental rats euthanazed 7 and 30 days. NADPH diaphorase staining revealed a significant decrease in nitric oxide synthase (NOS) containing nerve fibers in the dorsal and intracavernosal nerves in all rats in the experimental group. Electron microscopy showed a variety of changes such as collapse of sinusoids, increased cell debris, fibroblast and myofibroblast loss, intracellular deposition of fat and collagen and fatty degeneration. RT-PCR revealed up-regulation of TGF-beta1 after 3 days but not after 7 days or 1 month. There is no significant difference in IGF-I or FGF expression between the experimental and control group. Bilateral ligation of internal iliac arteries produces a reliable animal model for traumatic arteriogenic ED. Further studies are needed to investigate the molecular mechanism of ED in this model.

Animals↗
PubMed1999

A sustained rat model for studying the long-lasting catabolic state of sepsis.

Most animal models of sepsis induced high mortality or early recovery and do not mimic the long-lasting catabolic state observed in patients. The purpose of this study is to develop a model of sepsis which reproduces these disorders, especially the long-lasting muscle wasting. This report summarizes our observations in a series of seven experiments using this model with rats to study the route of live Escherichia coli administration, dose of bacteria, reproducibility of the model, bacterial count in tissues, comparison of injection of live or dead bacteria, metabolic perturbations linked to infection, and potential role of tumor necrosis factor alpha (TNF-alpha) in muscle wasting. After intravenous infection, animals were anorexic and the catabolic state was long-lasting: body weight loss for 2 to 3 days followed by a chronic wasting state for several days. Liver, spleen, lung protein content, and plasma concentration of alpha2-macroglobulin were increased 2 and 6 days after infection. At 6 days, muscle protein content was substantially (-40%) reduced. The plasma TNF-alpha level measured 1.5 h after infection correlated with body weight loss observed 9 days later. The inhibition of TNF-alpha secretion by administration of pentoxifylline 1 h before infection reduced muscle wasting and activation of proteolysis at day 2 and abolished them at day 6. This septic model mimics in rats the prolonged protein metabolism alterations and muscle atrophy characteristics of infected patients and thus is useful for studying the impact of nutritional support on outcome.

Animals↗
PubMed2005

Local application of rhTGF-beta2 enhances peri-implant bone volume and bone-implant contact in a rat model.

Orthopedic and dental implant fixation depends upon bone regeneration. Growth factors such as transforming growth factor-beta (TGF-beta) have been shown to enhance bone repair and strengthen the mechanical connection between implant and host skeleton in canine models. To provide a platform for studying molecular mechanisms of growth factor stimulated bone regeneration and implant fixation, the present study examined peri-implant bone volume as a response to TGF-beta treatment in a rodent model. The rat femoral ablation model in which an implant is placed in the medullary cavity of the femur was used to examine the dose response to TGF-beta2 applied to the implant (0, 0.1, 1.0, or 10 microg). The study included a total of 40 rats (10 per dose) examined at 28 days. Peri-implant bone volume and bone-implant contact were assessed through microcomputed tomography and implant fixation strength was determined by a mechanical pullout test. Treatment of the implant with 10 microg TGF-beta2 led to a 2-fold increase in bone volume (P<0.001) and a 1.5-fold increase in bone-implant contact (P<0.01) with a trend of increasing fixation strength (non-significant increase of 1.4-fold). TGF-beta2 treatment with 10 microg led to uniform peri-implant bone volume and bone-implant contact along the length of the implant, whereas the other groups had less bone at the mid-point compared to the proximal and distal aspects of the implant. About 50% of the variance in implant fixation strength was explained by a regression model involving both bone-implant contact and peri-implant bone volume.

Animals↗
PubMed2005

BMP-2 liberated from biomimetic implant coatings induces and sustains direct ossification in an ectopic rat model.

INTRODUCTION: Using a rat model, we evaluated the kinetics and histomorphometry of ectopic bone formation in association with biomimetic implant coatings containing BMP-2. MATERIALS AND METHODS: One experimental and three control groups were set up: titanium-alloy discs coated with a biomimetically co-precipitated layer of calcium phosphate and BMP-2 [1.7 microg per disc (incorporated-BMP group)]; uncoated discs (control); discs biomimetically coated with a layer of calcium phosphate alone (control); and discs biomimetically coated with a layer of calcium phosphate bearing superficially adsorbed BMP-2 [0.98 microg per disc (control)]. Discs (n = 6 per group) were implanted subcutaneously in rats and retrieved at 7-day intervals over a period of 5 weeks for kinetic, histomorphometrical, morphological and histochemical analyses. RESULTS: In the incorporated-BMP-2 group, osteogenic activity was first observed 2 weeks after implantation and thereafter continued unabated until the end of the monitoring period. The net weekly rates of bone formation per disc were 5.8 mm3 at 2 weeks and 3.64 mm3 at 5 weeks. The total volumes of bone formed per disc at these junctures were 5.8 mm3 and 10.3 mm3, respectively. Bone tissue, which was formed by a direct ossification mechanism, was deposited at distances of up to 340 microm from the implant surfaces. The biomimetic coatings were degraded gradually, initially by foreign body giant cells alone and then also by osteoclasts. Forty percent of the coating material (and thus presumably of the incorporated BMP-2) remained at the end of the monitoring period. Hence, 60% of the incorporated BMP-2 had been released. At this 5-week juncture, no bone tissue was associated with any of the control implants. CONCLUSION: BMP-2 incorporated into biomimetic calcium phosphate coatings is capable not only of inducing bone formation at an ectopic site in vivo but also of doing so with a very high potency at a low pharmacological level, and of sustaining this activity for a considerable period of time. The sustainment of osteogenic activity is of great clinical importance for the osseointegration of dental and orthopedic implants.

Acid Phosphatase↗
PubMed1991

Effect of glycine on retroperitoneal and intraperitoneal organs in the rat model.

Twenty Sprague Dawley rats were administered various doses of 1.5% amino acetic acid (glycine), lactated Ringer's, and water, both intravenously and retroperitoneally, in an attempt to recreate the post-transurethral resection syndrome in a rat model. The kidneys, liver, and pancreas were harvested 6 hours after exposure and examined pathologically. Water and lactated Ringer's had no histologic effect on these organs. Glycine was found to have a toxic effect on the kidneys and liver and this effect was dose related. Based on these results, it is postulated that glycine toxicity may play a significant role as a causative factor in producing the post-transurethral resection syndrome.

Animals↗
PubMed2003

Estrous changes in vaginal nociception in a rat model of endometriosis.

A rat model of endometriosis, in which pieces of uterine horn (versus fat in controls) are autotransplanted into the abdomen where they form cysts, reduces fecundity and produces vaginal hyperalgesia. The cysts gradually enlarge over a 2-month period postsurgically and then plateau. Cysts regress with low estrogen levels and reappear when they rise. Based on the hypothesis that the vaginal hyperalgesia depends upon the cysts, this study tested two predictions: that (1) the hyperalgesia would develop postsurgically in parallel with the cysts, and (2) the hyperalgesia would vary with estrous, being greatest when estrogen levels are high (proestrus) and least when low (estrus). In rats trained to escape vaginal distention, percentage escape responses to different distention volumes were measured across the rat's 4-day estrous cycle for 2.5 months before and up to 4 months after autotransplantation of uterus (n=9) or fat (n=6) in abdominal sites. Vaginal pressures were also measured. In rats with uterine but not fat autotransplants, escape percentages increased postsurgically over a 2-month period and then plateaued. The increase was greatest in proestrus and failed to occur in estrus. Vaginal pressures were unchanged in all groups. These results strongly support the hypothesis that the vaginal hyperalgesia depends upon the cysts. Because the cysts were located in sites remote from the vagina, the hyperalgesia involves viscero-visceral interactions and is likely centrally mediated, whereas the estrous modulation could involve hormonal actions either on the cysts or, more likely, on vaginal afferent fibers, and/or on central neurons.

Adipose Tissue↗
PubMed2004

Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog expression in abnormal ectopic notochord in the adriamycin rat model.

BACKGROUND/PURPOSE: The Adriamycin rat model (ARM) is a well-established model of the Vertebral, Anorectal, Cardiac, Tracheoesophageal, Renal, Limb (VACTERL) association. The notochord, which expresses Sonic Hedgehog (Shh), has been found to be grossly malformed with ventral ectopic branches in the foregut region of embryos in the ARM. The authors designed this study to test the hypothesis that Shh-expressing ectopic notochord could contribute to an increased volume of notochord relative to total embryo volume, resulting in an increased concentration of Shh in the notochord of affected embryos. METHODS: Adriamycin was administered intraperitoneally to rats on days 7 (E7), E8, and E9 of gestation and saline to control animals. Embryos recovered at E12 and E14 were examined immunohistochemically for Shh expression. Quantitative morphology using the Cavalieri technique was performed to determine embryo and notochord volume. RESULTS: Embryos in both Adriamycin and control groups at E12 and E14 showed comparable levels of Shh expression in notochord at all locations. The percentage of notochord per embryo was significantly increased in Adriamycin embryos at E12 and E14 compared with equivalent controls. CONCLUSIONS: These data suggest that Adriamycin induces notochord hypertrophy. With all regions of the notochord secreting Shh, this could result in a higher concentration gradient of Shh in close abnormal proximity to the foregut, possibly contributing to the malformations found in the VACTERL association.

Abnormalities, Drug-Induced↗
PubMed2004

Suppression and modulation of cellular and humoral immune responses to Haemophilus influenzae type B (Hib) conjugate vaccine in hib-diphtheria-tetanus toxoids-acellular pertussis combination vaccines: a study in a rat model.

We assessed a rat model to evaluate the immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines and the effect on Hib immunogenicity of combining 2 Hib vaccines (Hib-tetanus toxoid [TT]-A and Hib-TT-B) with diphtheria-TT-acellular pertussis (DTaP)(3) or DTaP(5)/inactivated poliovirus (IPV) vaccines. Rats were immunized subcutaneously with Hib alone or with Hib and DTaP-based vaccines; anti-Hib capsular polysaccharide IgG, poly-ribosyl-ribitol-phosphate (PRP), IgG subclass, and cellular immune responses were evaluated. Results showed a significant reduction in the antibody response to PRP when Hib-TT-A was administered in combination with DTaP(3) and showed changes in the anti-PRP IgG subclass distribution between the separate and combination groups. However, combining Hib-TT-B with DTaP(5)/IPV did not reduce the anti-PRP antibody response. These results suggest that the model can predict the effect of combined administration of Hib and DTaP vaccines on Hib immunogenicity and would be suitable for preclinical studies of mechanisms of interference in Hib/DTaP vaccines.

Animals↗
PubMed2001

The effect of methylene blue on histological damage after spermatic cord torsion in a rat model.

OBJECTIVE: To investigate, in a rat model, whether methylene blue (a free-radical scavenger) is effective in alleviating the histological testicular damage caused by reperfusion after spermatic cord torsion. MATERIALS AND METHODS: Male Wistar rats underwent a clockwise 720 degrees left spermatic cord torsion lasting 3 h; they were then randomly assigned to treatment and control groups. In the treated group, 2 mg/kg methylene blue was injected intraperitoneally 20 min before the cord was untwisted, and an additional 1 mg/kg injected into the penile vein 1--2 min beforehand. After 14 days, the left testicle was removed and assessed histologically. The control group was not treated. RESULTS: Thirty-three rats in the treatment group and 35 untreated controls were suitable for evaluation. Treatment with methylene blue was not significantly predictive of histological damage; the colour of the testis before detorsion was not correlated with histological damage. CONCLUSION: Anti-oxidant treatment with methylene blue had no palliative effect on the histological changes after torsion and detorsion of the spermatic cord in this rat model.

Animals↗
PubMed2002

[Evaluation of liver function with 13C-labelled amino acid using hepatectomized rat model].

UNLABELLED: Using a rat model of hepatectomy, we investigated whether the severity of hepatopathy could be quantitatively measured from changes in expiratory 13CO2 levels after intravenous administration of L-[1-(13)C]phenylalanine, L-[1-(13)C]methionine or L-[1-(13)C]alanine. MATERIALS AND METHODS: Under nembutal anesthesia, 30 mg/kg L-[1-(13)C]phenylalanine, 40 mg/kg L-[1-(13)C]methionine or 20 mg/kg L-[1-(13)C]alanine was administered to rats through the femoral vein, and expiratory 13CO2 levels were measured for 15 min. Thirty percent, 70% or 90% hepatectomy was performed. In the control group, simple laparotomy was performed. RESULTS: The correlation coefficient between total 13CO2 output over 15 min after L-[1-(13)C]phenylalanine administration and liver weight/body weight was 0.883 (P < 0.001). The correlation coefficient between total 13CO2 output over 15 min after L-[1-(13)C]methionine administration and liver weight/body weight was 0.922 (P < 0.001). The correlation coefficient between total 13CO2 output over 15 min after L-[1-(13)C]alanine administration and liver weight/body weight was 0.902 (P < 0.0001). CONCLUSION: In the breath test with intravenously administered L-[1-(13)C]phenylalanine, L-[1-(13)C]methionine, or L-[1-(13)C]alanine, hepatopathy could be quantitatively evaluated by measuring expiratory 13CO2 levels over 15 min.

Alanine↗
PubMed2006

Pharmacokinetics of diclofenac in rat model of diabetes mellitus induced by alloxan or steptozotocin.

The pharmacokinetics of diclofenac were compared after intravenous and oral administration at a dose of 5 mg/kg in a rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. Diclofenac was reported to be metabolized via the hepatic microsomal cytochrome P450 (CYP) 2C11 in male rats. The expression and mRNA level of CYP2C11 decreased in rat models of DMIA and DMIS. Hence, the time-averaged nonrenal clearance (Clnr) of diclofenac was expected to be slower in a rat model of diabetes. As expected, after intravenous administration, the Clnr values of diclofenac were significantly slower in rat models of DMIA (11.3 versus 13.6 ml/min/kg) and DMIS (8.06 versus 15.2 ml/min/kg) than those in control rats. As a result, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were significantly greater in rat models of DMIA (435 versus 367 microg min/ml) and DMIS (540 versus 329 microg min/ml). However, after oral administration, the AUC from time zero to the last measured time, 12 h, in plasma (AUC0-12 h) values were comparable between the rat models of DMIA and DMIS and their control rats, and this could be due to changes in the first-pass effect of diclofenac and was not due to a decrease in the absorption of diclofenac in the rat models of diabetes.

Administration, Oral↗
PubMed2001

Comparison of PDE 4 inhibitors, rolipram and SB 207499 (ariflo), in a rat model of pulmonary neutrophilia.

Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.

Adrenalectomy↗
PubMed2005

A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models.

The purpose of this paper is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, (abbreviated as ZMS in this paper), on learning ability and memory of three animal models: aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1-40 (Abeta1-40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step-through test revealed that learning ability and memory were impaired in the three models and were improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase nor did it occupy the binding sites of muscarinic acetylcholine receptor (M receptor), hence it is neither an cholinesterase inhibitor nor an agonist or antagonist of M receptors. On the other hand, the densities of total M receptor and its M1 subtype in the brain of the three models were significantly lower than control rats, and ZMS significantly raised the densities of total M receptors and its M1 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M1 subtype. Autoradiographic study with 3H-pirenzipine showed that the M1 subtype density was significantly lowered in cortex, hippocampus and striatum of aged rats, and ZMS could reverse these changes towards normal control level. Interestingly, the M1 receptor density after ZMS administration only approached but did not exceed that of normal young control rats. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease.

Acetylcholinesterase↗