Abstract 169: Human Dose tPA Improves Functional Outcomes in Both Sexes in Embolic Model of Stroke: Differential Effect on Hemorrhagic Transformation

Tissue plasminogen activator (tPA) is the only FDA-approved therapeutic agent for the treatment of acute ischemic stroke. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT) and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low dose tPA would achieve clot lysis, decrease neurovascular injury and improve functional outcomes in both sexes. Aged-matched male and female Wistar rats (n=5-7) have been treated with or without tPA (1 mg/kg, i.v.) at 90 min after embolic middle cerebral artery occlusion with a fibrin-rich humanized clot. The neurological deficiency (Bederson score and adhesive removal test -ART), infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). Compared to male rats, female rats had smaller infarct size and better functional outcomes as previously reported in the literature. tPA decreased infarct size in both sexes. tPA reduced edema in males with no effect in females. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. Functional outcomes, especially ART, were significantly improved with tPA in both sexes. These data suggest that 1) thrombolysis with a low dose tPA is effective in improving short term outcomes in both sexes, and 2) better functional outcomes in females are further enhanced with tPA. Additional studies are in progress to explore long term effects and the impact of therapeutic window, age and sex steroids on outcomes as well as the underlying mechanisms contributing to less HT in females.

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Vulnerability factors for mephedrone-induced conditioned place preference in rats—the impact of sex differences, social-conditioning and stress

Psychopharmacology ◽

10.1007/s00213-021-05910-y ◽

2021 ◽

Author(s):

Olga Wronikowska ◽

Maria Zykubek ◽

Łukasz Kurach ◽

Agnieszka Michalak ◽

Anna Boguszewska-Czubara ◽

...

Keyword(s):

Sex Differences ◽

Conditioned Place Preference ◽

Low Dose ◽

Social Factor ◽

Place Preference ◽

Female Rats ◽

Male Rats ◽

Social Conditioning ◽

Male And Female Rats ◽

The Impact

Abstract Rationale Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood. Objectives The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress — CMUS) on the liability to mephedrone-induced reward in Wistar rats. Methods The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively. Results Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats’ prefrontal cortex and hippocampus. Conclusions Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.

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Abstract W MP96: Low Dose Tissue Plasminogen Activator Amplifies Vascular Injury and Worsens Functional Outcomes in Acute Hyperglycemic Stroke Independent of the Model of Reperfusion

Stroke ◽

10.1161/str.46.suppl_1.wmp96 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Sherif Hafez ◽

Md Nasrul Hoda ◽

Xinyue Guo ◽

Susan Fagan ◽

Adviye Ergul

Keyword(s):

Infarct Size ◽

Vascular Injury ◽

Functional Outcomes ◽

Low Dose ◽

Hemorrhagic Transformation ◽

Occurrence Rate ◽

Translational Study ◽

Flow Monitoring ◽

Tissue Plasminogen ◽

Tissue Hemoglobin

Clinically, hyperglycemia (HG) exacerbates reperfusion injury and aggravates tPA-induced hemorrhagic transformation (HT). Yet, most of the experimental hyperglycemic stroke studies exclusively employed suture occlusion model. Only few studies involved tPA in hyperglycemic setting and employed a 10-fold higher dose of tPA than that is used in patients. Thus, in this translational study using suture and thromboembolic occlusion of middle cerebral artery (MCA), with and without human tPA dose, we tested the hypothesis that even acute mild HG worsens the neurovascular injury and functional outcomes irrespective of the method of reperfusion, and that the use of low dose tPA amplifies this injury. Methods: Control and mildly HG rats (140-200 mg/dl, achieved by 30% glucose ip injection 15 min prior to surgery, n=7-9/group) were subjected to MCA occlusion by either suture (90 min) or humanized clot and 24 h reperfusion. tPA (1mg/kg) was injected IV 2 h after induction of ischemia. At 24 h, neurological deficit, infarct size, edema, HT occurrence rate (HT index) and tissue hemoglobin (Hb) were measured. Results: Cerebral blood flow monitoring indicated that % drop at occlusion were similar across the groups and that low dose tPA effectively resolved the clot in the embolic model. tPA did not increase the infarct size in either control or hyperglycemic animals when compared to no tPA groups (Table). HG increased vascular injury (HT index and Hb content) in both suture and embolic occlusion models. The combination of HG and tPA exacerbated the vascular injury and worsened functional outcomes more than each alone. Conclusion: The interaction between HG and even low dose tPA has a significant deleterious effect on cerebrovasculature and functional outcomes independent of the method of reperfusion.

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Abstract TP277: Diabetes Amplifies Vascular Injury and Worsens Ischemic Stroke Outcome in Young Female Rats: Loss of Protection

Stroke ◽

10.1161/str.47.suppl_1.tp277 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

John P Valenzuela ◽

Weiguo Li ◽

Yasir Abdul ◽

Rebecca Ward ◽

Sally El-Shafey ◽

...

Keyword(s):

Infarct Size ◽

Hemorrhagic Transformation ◽

Young Female ◽

Female Rats ◽

Male Rats ◽

Neurological Deficits ◽

Control Group ◽

Stroke Outcome ◽

Long Term Effects ◽

Male And Female Rats

Women are protected from stroke until they reach menopause in part due to neuroprotection conferred by sex hormones. We and others have shown that that diabetes increases neurovascular injury and worsens stroke outcomes in males. Given the clinical evidence that diabetes increases stroke risk especially in younger individuals and females, we hypothesized that diabetes worsens stroke outcome even in young females. We further postulated that moderate hyperglycemia worsens hemorrhagic transformation (HT) and outcomes independent of changes in infarct size. High fat diet plus low dose streptozotocin model of diabetes was used. Control and diabetic weight-matched male and female rats (10-12 weeks old, n=5-7) were subjected to embolic stroke with a fibrin-rich humanized clot. Neurological deficits (Bederson score, adhesive removal test -ART and grip strength), infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). As expected in the control group, females rats had smaller infarct size, less edema, and better functional outcomes as compared to male rats. In the diabetic group, however, HT score was greater and this was more profound in females. Diabetes worsened the functional outcome to a much greater extent in females. While there was partial improvement of neurological deficits by Day 3 in control animals, diabetic animals did not improve but worsened. Additional studies will explore the long-term effects and the underlying mechanisms contributing to worse outcome in young and old diabetic females.

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Perinatal exposure to a low dose of bisphenol-A advances pubertal spermatogenesis of F1 adolescent male rats

10.21203/rs.3.rs-72109/v1 ◽

2020 ◽

Author(s):

Yinyang Bai ◽

Fang Xiong ◽

Yun Zhang ◽

Jie Chen ◽

Lishuang Xu ◽

...

Keyword(s):

Bisphenol A ◽

Plasma Levels ◽

Low Dose ◽

Male Offspring ◽

Female Rats ◽

Male Rats ◽

Seminiferous Tubules ◽

Perinatal Exposure ◽

Significant Difference ◽

The Impact

Abstract Background To investigate the impact of perinatal exposure to a low dose of bisphenol A (BPA) on spermatogenesis in male rats and the underlying mechanism. Methods Female rats were injected subcutaneously with 2 µg BPA/kg/day from gestation day 10 through lactation day 7. The spermatogenesis and expression of key regulatory genes in the testes as well as the central modulators of the hypothalamic-pituitary-gonadal axis were determined in male offspring on postnatal day 18, 21, and 24 (PND18, 21, and 24). Results 1) Perinatal BPA exposure led to an increase in the weight of body and testis in PND21-24 male offspring. The seminiferous tubular diameter and the number of round spermatids were significantly increased in PND21 BPA-rats, while the volumes of the Sertoli cells, spermatogonia and spermatocytes were not significantly altered. 2) Compared to the control rats, the expression levels of key meiotic regulators such as cyclinA1, c-jun and c-fos in the seminiferous tubules were significantly elevated in PND21 BPA-rats. 3) The plasma levels of FSH and LH (PND21 and PND24) as well as the frequency of pulsatile LH secretion (PND21) were significantly increased in BPA-rats, although the plasma levels of testosterone and estrogen showed no significant difference between the two groups. 4) In comparison with control rats, the levels of GnRH mRNA in the preoptic area (POA) and kiss1 mRNA in arcuate nucleus (ARC) were significantly increased in the BPA-rats, whereas the level of ERα mRNA in ARC was decreased, although the number of GnRH-positive cells and ARC kisspeptin-positive cells were unchanged. Interestingly, neither the number of kisspeptin-positive cells nor the level of kiss1 mRNA in the anteroventral periventricular nucleus (AVPV) showed a difference between the two groups. Conclusion Perinatal exposed to a low dose of BPA leads to an increased meiosis of spermatocytes and promotes the spermatogenesis in male offspring, most likely through activation of the hypothalamic-pituitary-gonadal axis.

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Male gender increases sensitivity to renal injury in response to cholesterol loading

AJP Renal Physiology ◽

10.1152/ajprenal.00009.2002 ◽

2003 ◽

Vol 284 (4) ◽

pp. F718-F726 ◽

Cited By ~ 17

Author(s):

Diana M. Attia ◽

Roel Goldschmeding ◽

Mahmoud A. Attia ◽

Peter Boer ◽

Hein A. Koomans ◽

...

Keyword(s):

Renal Injury ◽

Low Dose ◽

Plasma Cholesterol ◽

A Priori ◽

No Synthase ◽

Male Gender ◽

Female Rats ◽

Male Rats ◽

High Dose ◽

Cholesterol Feeding

Males are at greater risk for renal injury than females. This may relate to nitric oxide (NO) availability, because female rats have higher renal endothelial NO synthase (NOS) levels. Previously, our laboratory found susceptibility to proteinuria induced by NOS inhibition in male compared with female rats. Dyslipidemia and hypercholesterolemia dose dependently decreased renal NOS activity and caused renal injury in female rats. We hypothesized that exposure of male rats to hypercholesterolemia would lead to more renal injury in male than in female rats due to an a priori lower renal NO system. Female and male rats were fed no, low-dose, or high-dose cholesterol for 24 wk. Cholesterol feeding dose dependently increased proteinuria in both female and male rats, but male rats developed more proteinuria at similar plasma cholesterol ( P < 0.001). Control males had lower renal NOS activity than control females (4.44 ± 0.18 vs. 7.46 ± 0.37 pmol · min−1 · mg protein−1; P < 0.05), and cholesterol feeding decreased renal NOS activity in males and in females ( P < 0.05). Cholesterol-fed males developed significantly more vascular, glomerular, and tubulointerstitial monocyte/macrophage influx and injury than females. Thus under baseline conditions, male rats have lower renal NOS activity than female rats. This may explain why male rats are more sensitive to renal injury by factors that decrease NO availability, such as hypercholesterolemia.

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Effectiveness of Combined External Ventricular Drainage with Intraventricular Fibrinolysis for the Treatment of Intraventricular Haemorrhage with Acute Obstructive Hydrocephalus

Cerebrovascular Diseases Extra ◽

10.1159/000501530 ◽

2019 ◽

Vol 9 (2) ◽

pp. 77-89 ◽

Cited By ~ 3

Author(s):

Chinh Quoc Luong ◽

Anh Dat Nguyen ◽

Chi Van Nguyen ◽

Ton Duy Mai ◽

Tuan Anh Nguyen ◽

...

Keyword(s):

Functional Outcome ◽

Functional Outcomes ◽

Low Dose ◽

Obstructive Hydrocephalus ◽

Intraventricular Haemorrhage ◽

External Ventricular Drainage ◽

Risk Of Death ◽

Good Functional Outcome ◽

Intraventricular Fibrinolysis ◽

The Impact

Background: Intraventricular haemorrhage (IVH) patients with acute obstructive hydrocephalus (AOH) who require external ventricular drainage (EVD) are at high risk for poor outcomes. Intraventricular fibrinolysis (IVF) with low-dose recombinant tissue plasminogen activator (rtPA) can be used to improve patient outcomes. Here, we evaluated the impact of IVF on the risk of death and the functional outcomes in IVH patients with AOH. Methods: This prospective cohort study included IVH patients with hypertensive intracranial haemorrhage complicated by AOH who required EVD. We evaluated the risk of death and the functional outcomes at 1 and 3 months, with a specific focus on the impact of combined EVD with IVF by low-dose rtPA. Results: Between November 30, 2011 and December 30, 2014, 80 patients were included. Forty-five patients were treated with EVD alone (EVD group) and 35 received IVF (EVD+IVF group). The 30- and 90-day mortality rates were lower in the EVD+IVF group than in the EVD group (42.2 vs. 11.4%, p = 0.003, and 62.2 vs. 20%, p < 0.001, respectively). The Graeb scores were significantly lower in the EVD+IVF group than in the EVD group (p ≤ 0.001) during the first 3 days and on day 7 after assignment. The 30-day good functional outcome (modified Rankin Scale [mRS] score 0–3) was also higher in the EVD+IVF group than in the EVD group (6.7 vs. 28.6%, p = 0.008). However, the 90-day good functional outcome (mRS score 0–3) did not significantly increase in the EVD+IVF group (30.8% in the EVD group vs. 51.6% in the EVD+IVF group, p = 0.112). Conclusions: In our prospective observational study, EVD+IVF was associated with a lower risk of death in IVH patients. EVD+IVF improved the chance of having a good functional outcome at 1 month; however, this result was no longer observed at 3 months.

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Effects of rearing temperature on body weight and abdominal fat in male and female rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.2.r398 ◽

1998 ◽

Vol 274 (2) ◽

pp. R398-R405 ◽

Cited By ~ 8

Author(s):

James B. Young ◽

Yasunobu Shimano

Keyword(s):

Weight Gain ◽

Later Life ◽

Female Rats ◽

Male Rats ◽

Fat Accumulation ◽

Rearing Temperature ◽

Male And Female Rats ◽

Postnatal Environment ◽

Temperature Exposure ◽

The Impact

Thermoregulatory mechanisms are influenced by the temperature of the postnatal environment. Animals reared in cool environments are more tolerant of cold as adults, whereas those reared in warm conditions are more tolerant of heat. Because diet-induced and thermoregulatory thermogenesis share common features, studies examined the impact of rearing temperature on weight gain and fat accumulation. Rats reared at 18°C gained more weight and accumulated more fat in abdominal depots than animals reared at 30°C when both were housed at a common temperature, responses that were exacerbated by ad libitum access to sucrose. Male rats reared at 30°C were less affected by sucrose than 18°C-reared males, whereas female rats reared at 18 or 30°C were similarly susceptible. During exposure to 18°C, fat accumulation in abdominal depots increased in males but decreased in females. These data suggest that early temperature exposure influences weight gain and fat accumulation in later life, a difference that is most apparent when animals are housed at a common temperature.

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High-fat diet-induced hypertension is associated with a proinflammatory T cell profile in male and female Dahl salt-sensitive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00389.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. H1713-H1723 ◽

Cited By ~ 13

Author(s):

Lia E. Taylor ◽

Ellen E. Gillis ◽

Jacqueline B. Musall ◽

Babak Baban ◽

Jennifer C. Sullivan

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

High Fat Diet ◽

Female Rats ◽

Male Rats ◽

High Fat ◽

Male And Female ◽

The Impact ◽

Cell Profile

Evidence supports a sex difference in the impact of a high-fat diet (HFD) on cardiovascular outcomes, with male experimental animals exhibiting greater increases in blood pressure (BP) than female experimental animals. The immune system has been implicated in HFD-induced increases in BP, and there is a sex difference in T-cell activation in hypertension. The goal of this study was to determine the impact of HFD on BP and aortic and renal T cell profiles in male and female Dahl salt-sensitive (DSS) rats. We hypothesized that male DSS rats would have greater increases in BP and T cell infiltration in response to a HFD compared with female DSS rats. BP was measured by tail-cuff plethysmography, and aortic and renal T cells were assessed by flow cytometric analysis in male and female DSS rats on a normal-fat diet (NFD) or HFD from 12 to 16 wk of age. Four weeks of HFD increased BP in male and female DSS rats to a similar degree. Increases in BP were accompanied by increased percentages of CD4+ T cells and T helper (Th)17 cells in both sexes, although male rats had more proinflammatory T cells. Percentages of renal CD3+ and CD4+ T cells as well as Th17 cells were increased in both sexes by the HFD, although the increase in CD3+ T cells was greater in male rats. HFD also decreased the percentage of aortic and renal regulatory T cells in both sexes, although female rats maintained more regulatory T cells than male rats regardless of diet. In conclusion, both male and female DSS rats exhibit BP sensitivity to a HFD; however, the mechanisms mediating HFD-induced increases in BP may be distinct as male rats exhibit greater increases in the percentage of proinflammatory T cells than female rats. NEW & NOTEWORTHY Our study demonstrates that male and female Dahl salt-sensitive rats exhibit similar increases in blood pressure to a high-fat diet and an increase in aortic and renal T cells. These results are in contrast to studies showing that female rats remain normotensive and/or upregulate regulatory T cells in response to hypertensive stimuli compared with male rats. Our data suggest that a 4-wk high-fat diet has sex-specific effects on the T cell profile in Dahl salt-sensitive rats.

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Carcinogenesis Bioassay of Propyl Gallate in F344 Rats and B6C3FJ Mice

Journal of the American College of Toxicology ◽

10.3109/10915818309140729 ◽

1983 ◽

Vol 2 (6) ◽

pp. 425-433 ◽

Cited By ~ 12

Author(s):

K. M. Abdo ◽

J. E. Huff ◽

J. K. Haseman ◽

M. P. Dieter ◽

G. A. Boorman ◽

...

Keyword(s):

Propyl Gallate ◽

Dose Group ◽

Low Dose ◽

Female Rats ◽

Male Rats ◽

High Dose Group ◽

High Dose ◽

Preputial Gland ◽

Rats And Mice ◽

F344 Rats

Chronic toxicity studies were conducted by maintaining groups of 50 F344 rats and 50 B6C3F1 mice of each sex on nutritionally complete diets containing 0%, 0.6%, or 1.2% propyl gallate for 103 weeks. Survival of rats and mice of both sexes was not significantly affected by the administration of this compound. Dosed rats and mice showed growth retardation and reduced feed utilization efficiency. Increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland were observed in dosed male rats and were considered to be related to propyl gallate administration. Tumors of the preputial gland, islet ceil tumors of the pancreas, and pheochromocytoma of the adrenal gland were observed with significantly (p < 0.05) higher incidence in the low-dose male rats; however, there was little evidence of a dose response or of an effect in the high-dose group. Rare tumors (an astrocytoma and a glioma) were found in the brains of two low-dose female rats but none was found in the high-dose group. Malignant lymphoma occurred with a significant (p < 0.05) positive trend in male mice and the incidence in the high-dose group was significantly (p < 0.05) higher than that of the concurrent controls. However, the high-dose incidence was not significantly different from the historical control rate for the laboratory that conducted the bioassay. Under the conditions of the bioassay, propyl gallate was not considered to be clearly carcinogenic for F344 rats, although the increased incidence of preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytoma of the adrenal glands in low-dose male rats may have been related to compound administration. Thus, the evidence for carcinogenicity in male rats is regarded as being equivocal, while there was no indication of a carcinogenic response in female rats. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice, although the increased incidence of malignant lymphoma in dosed male mice may have been related to administration of the test compound.

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Subchronic Toxicological Assessment of Dr Iguedo Goko Cleanser® on Lipid Profile and Serum Antioxidant Enzymes in Exposed Wistar Rats

Asian Journal of Biology ◽

10.9734/ajob/2020/v9i430093 ◽

2020 ◽

pp. 16-25

Author(s):

Godswill J. Udom ◽

Jude E. Okokon ◽

John A. Udobang ◽

Daniel N. Obot ◽

Nkechi J. Onyeukwu

Keyword(s):

Oxidative Stress ◽

Lipid Profile ◽

Wistar Rats ◽

Low Dose ◽

Herbal Remedy ◽

Female Rats ◽

Male Rats ◽

High Density Lipoproteins ◽

High Dose ◽

Low Density

Dr Iguedo Goko Cleanser® is a polyherbal mixture promoted as an effective herbal remedy for numerous diseases. Study aimed to evaluate the toxicity concern of the polyherbal mixture (PHM) on lipid profile and oxidative status in Wistar rats of both gender. Acute toxicity study was conducted using modified method of Lorke. Thirty Wistar rats of bother gender were randomly divided into six groups (5/group) and exposed to the polyherbal mixture for 60 days via oral gavage. Control groups (1 and 4) received 10 mL/kg distilled water, while groups 2-3 and 5-6 received 476.24 and 158.75 mg/kg body weight of Dr Iguedo Goko Cleanser® respectively. On 62nd day, animals were sacrificed under diethyl ether anaesthesia; blood samples were collected by cardiac puncture for biochemical analysis. PHM significantly (p < 0.05) increased high density lipoproteins (HDL) levels in male rats as well as high dose female rats relative to control. However, low dose female rats recorded low HDL levels relative to control. Total cholesterol, triglycerides, low density and very low density lipoprotein levels were significantly reduced in all test groups relative to controls. The low dose males (LDM) had reduced serum glutathione peroxidase (GPX) activity; while increased and decreased GPX and glutathione (GSH) activities were respectively recorded for female rats. Male rats had dose-dependent increase in malondialdehyde. The recorded reductions in serum lipids suggest that the polyherbal mixture may have hypolipidemic potentials. While the increased malondialdehyde as well as decreased GPX and GSH indicate lipid peroxidation and oxidative stress inducing potentials of the PHM. Despite the positive modulation on lipid profile, findings suggest utmost caution on chronic use as its oxidative stress inducing potentials is considerable.

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