scholarly journals The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shoshana Buckhalter ◽  
Eric Soubeyrand ◽  
Sarah A.E. Ferrone ◽  
Duncan J. Rasmussen ◽  
Joshua D. Manduca ◽  
...  
Keyword(s):  
Low Dose ◽  
Repeated Administration ◽  
Male Rats ◽  
High Dose ◽  
Drug Induced ◽  
Theta Power ◽  
Oscillatory Systems ◽  
Delta Power ◽  
Gamma Power ◽  
Induced Changes

Mitragyna speciosa (“kratom”), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.

Excitation of Putative Glutamatergic Neurons in the Rat Parabrachial Nucleus Region Reduces Delta Power during Dexmedetomidine but not Ketamine Anesthesia

2021 ◽  
Author(s):  
Eric D. Melonakos ◽  
Morgan J. Siegmann ◽  
Charles Rey ◽  
Christopher O’Brien ◽  
Ksenia K. Nikolaeva ◽  
...  
Keyword(s):  
Recovery Time ◽  
Low Dose ◽  
Designer Drugs ◽  
Male Rats ◽  
Parabrachial Nucleus ◽  
High Dose ◽  
Median Difference ◽  
Delta Power ◽  
Calcium Calmodulin Dependent ◽  
Ketamine Anesthesia

Background Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia. Methods Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin–dependent protein kinase 2α–positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg−1 · min−1 for 45 min, eight rats; high dose: 4.5 µg · kg−1 · min−1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg−1 · min−1 for 30 min, seven rats; high dose: 4 mg · kg−1 · min−1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed. Results Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide – saline] during dexmedetomidine infusion = −6.06 [99% CI = −12.36 to −1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [−1.93, −0.87] dB, 99% CI = [−4.16 to −0.56, −1.62 to −0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [−20.06 to 14.14, −20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: −3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016). Conclusions These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic’s molecular target. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Myoclonus Due to Chlorambucil in Two Adults with Lymphoma

1997 ◽  
Vol 31 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Andrew Rj Wyllie ◽  
Charles D Bayliff ◽  
Michael J Kovacs
Keyword(s):  
Nephrotic Syndrome ◽  
Science Citation Index ◽  
Low Dose ◽  
Citation Index ◽  
Science Citation ◽  
Data Sources ◽  
High Dose ◽  
Drug Induced ◽  
Neurologic Status ◽  
Subsequent Decrease

Objective To report myoclonus due to chlorambucil therapy in two adults with lymphoma, and to review the literature of chlorambucil neurotoxicity in adults. Case Summaries Case 1: An 81-year-old man with lymphoma being treated with chlorambucil developed jerking movements and stiffness that persisted for 3 days and intensified at night. The dosage of chlorambucil was decreased with a subsequent decrease in symptomatology. Resolution of the myoclonus occurred with discontinuation of the chlorambucil. Rechallenge evoked a return of tremors the next day that later became constant and again resolved on discontinuation of chlorambucil. Case 2: A 75-year-old woman with lymphoma being treated with chlorambucil developed jerking movements in her limbs, particularly in her arms and right hip. The symptoms were so severe they prevented the patient from leaving her house. All symptoms resolved within 2–3 days after the cycle was completed and did not return. She was diagnosed as having had chlorambucil-induced myoclonus. Data Sources Searches were performed on MEDLINE, CancerLit, and Science Citation Index Review to identify reports and articles discussing chlorambucil-induced neurotoxicity, particularly myoclonus. Discussion Chlorambucil-induced myoclonus has been described in overdose situations and in the treatment of nephrotic syndrome in children. Three cases of reversible myoclonic activity associated with high-dose chlorambucil in adults have also been described. In each case, the myoclonus resolved following discontinuation of the drug. Only one other conclusive case of low-dose chlorambucil-induced myoclonus in an adult has been described. The two cases presented here are unique in that the myoclonus occurred in adults receiving low-dose chlorambucil who had no myoclonus before or after treatment with the drug. Conclusions From the cases reviewed, it appears that chlorambucil may induce myoclonus in adults receiving therapeutic dosages of chlorambucil. The neurologic status of patients receiving chlorambucil should be followed closely during treatment. If myoclonus develops, drug-induced myoclonus should be considered, as well as discontinuation of the drug.

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

2003 ◽  
Vol 284 (4) ◽  
pp. F718-F726 ◽  
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.

Influence of doxorubicin on lipid peroxidation and heart histology in rats

2015 ◽  
Vol 21 (31) ◽  
pp. 33-36
Author(s):  
Джиоев ◽  
Inal Dzhioev ◽  
Джанаев ◽  
Robert Dzhanaev
Keyword(s):  
Low Dose ◽  
Male Rats ◽  
Control Group ◽  
High Dose ◽  
Cardiovascular Toxicity ◽  
Anthracycline Antibiotic ◽  
Cross Striation ◽  
Group A ◽  
Sexually Mature ◽  
Experimental Group

Anthracycline antibiotic doxorubicin, which has proven cardiovascular toxicity, is often used in the treatment of cancer. The research project was carried out in 21 sexually mature Wistar male rats divided into three groups: control group, high-dose experimental group, in which rats were once injected intraperitoneally with doxorubicin hydrochloride at a dose of 10 mg/kg and low-dose experimental group, in which animals twice received intraperitoneal 2.5 mg/kg doses of doxorubicinhydrochloride at 10-day interval.An increase of malondialdehyde was revealed in the membranes of red blood cells in the high-dose experimental group, while in the low-dose experimental group a reduction in the levels of malondialdehyde and plasma hydroperoxides as well as a decreasing of catalase activity was observed. Intake of doxorubicin also causes venous hyperemia in wide areas of myocardiumalong with increasing of cardiomyocytic cross striation.

Carcinogenesis Bioassay of Propyl Gallate in F344 Rats and B6C3FJ Mice

1983 ◽  
Vol 2 (6) ◽  
pp. 425-433 ◽  
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.

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

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.

scholarly journals Effects of Vitamin E Supplementation in Male Rats with Crude Oil-Induced Reproductive Toxicity

2017 ◽  
Vol 9 (3) ◽  
pp. 332-337
Author(s):  
Izuchukwu S. OCHIOGU ◽  
Udensi M. IGWEBUIKE ◽  
Edmund C. MBEGBU ◽  
Ikenna O. EZEH ◽  
Paschal F. NNAMANI
Keyword(s):  
Vitamin E ◽  
Crude Oil ◽  
Dose Group ◽  
Low Dose ◽  
Reproductive Toxicity ◽  
Male Rats ◽  
High Dose ◽  
Serum Total Protein ◽  
The Mean ◽  
Vitamin E Supplementation

Crude oil intoxication is a major threat among people and animals living around the crude oil producing regions of the world, hence the search for ameliorating agents. Forty-four male Wistar rats assigned into three groups were used to investigate the effects of vitamin E supplementation on crude oil-induced reprotoxicity (reproductive toxicity) in male rats. Group A represented the unexposed control, whereas groups B and C were exposed orally to 0.15 and 0.3 ml of crude oil respectively every other day for 56 days. Both the low dose and high dose oral administration of crude oil caused a significant reduction in the serum testosterone level (STL) and cauda epididymal sperm reserve (CESR) of the exposed rats when compared to the control. Crude oil withdrawal and vitamin E supplementation significantly improved the cauda epididymal sperm reserve (CESR) in all the subgroups. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities of the control and low dose group were significantly lower than those of the high dose group. The high dose crude oil administration significantly decreased the mean serum total protein (STP) and sodium ions (Na+) concentration. The mean serum total cholesterol (STC) value of the low dose group was significantly higher than those of the control and high dose group. However, crude oil withdrawal and vitamin E supplementation did not significantly alter the mean serum total protein (STP) and mean serum total cholesterol (STC) values in all the subgroups. Vitamin E supplementation following low dose crude oil withdrawal enhanced the mean serum Chloride ions (Cl-)concentration. The present findings revealed that Nigerian Qua Iboe Brent crude oil induced serious reprotoxic effects in male rats which vitamin E administration within 28 days did not completely reverse. 

Interaction of ANP with endothelin on cardiovascular, renal, and endocrine function

1992 ◽  
Vol 262 (2) ◽  
pp. E135-E141 ◽  
Author(s):  
K. Ota ◽  
T. Kimura ◽  
M. Shoji ◽  
M. Inoue ◽  
K. Sato ◽  
...  
Keyword(s):  
Low Dose ◽  
Renal Plasma Flow ◽  
Peripheral Resistance ◽  
Plasma Renin ◽  
Endocrine Function ◽  
Molar Ratio ◽  
High Dose ◽  
Anesthetized Dogs ◽  
Induced Changes ◽  
Renal Responses

To assess the interaction of endothelin (ET) with atrial natriuretic peptide (ANP) on cardiovascular and renal function, arginine vasopressin (AVP) release, and the renin-angiotensin-aldosterone system, either a low or high dose of ET (4 or 12 pmol.kg-1.min-1) was administered with ANP (26 pmol.kg-1.min-1) for 45 min after the initial infusion of ANP alone in anesthetized dogs. In the other groups, either ANP or saline alone was administered for 90 min. ANP alone decreased blood pressure (BP), cardiac output (CO), plasma aldosterone, and plasma renin activity (PRA), increased urinary Na and K excretion (UNaV and UKV, respectively) and urine flow (UF), but did not affect plasma AVP. The low dose of ET had no effect on these ANP-induced changes. However, the high dose of ET curtailed the responses to ANP, increased BP and PRA, and decreased UNaV, UKV, and UF associated with decreased renal plasma flow and glomerular filtration rate. High ET also further potentiated the decrease in CO and the increase in total peripheral resistance induced by ANP and increased plasma AVP. These results indicate that a dose of ET one-half that of ANP (on the molar ratio) may have completely counteracted vascular, hormonal, and renal responses to ANP.

Gender difference in arsenic biotransformation is an important metabolic basis for arsenic toxicity

2021 ◽  
Author(s):  
Maihaba Muhetaer ◽  
Mei Yang ◽  
Rongxiang Xia ◽  
Jun Wu
Keyword(s):  
Gender Differences ◽  
Dose Group ◽  
Low Dose ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Arsenic Toxicity ◽  
Male And Female ◽  
Significant Difference ◽  
Medium Dose

Abstract Background: There are gender differences in the biotransformation of arsenic. We investigated the effects of gender differences on arsenic metabolism and arsenic toxicity mechanisms in rat liver tissues. Methods: Rats were treated with different amounts of arsenic compounds. Arsenic form MMA and DMA in the liver was determined by high performance liquid chromatography-hydride generation atomic fluorescence spectroscopy. SAM, ARR, NAD, PNP, PK, and MPO in rat liver were determined by enzyme-linked immunoassay. RT-qPCR was used to determine AS3MT in the liver. Results: Compared with male and female animals in the same group, MMA and DMA were statistically significant in the three groups of iAs3 + high, iAs3 + medium and iAs5+ low (P <0.05). The MMA of male rats in iAs3+ high and medium groups was higher than that of female rats, and the DMA of male rats was lower than that of female rats. As3MT mRNA in the male iAs3+ high group was higher than that of females. Besides, compared between male and female, only in iAS3+ low dose, iAS3+ medium dose, iAS5+ low dose, and iAS5+ medium dose groups, there was significant difference in SAM level (P<0.05). Compared with male and female animals in the same group, male rats had significantly higher PNP and ARR activities while lower PK activity than female rats (P<0.05). Between the male and female groups, only the iAS3+ high dose and medium dose group had a statistically significant difference (P<0.05). The NAD activity of females in iAS3+ high dose group was higher than that of males. Conclusion: Conclusively, under the same arsenic exposure, there were gender differences between female and male rats, and arsenic metabolism was more cytotoxic to male rats than to females.

scholarly journals Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats

2021 ◽  
Author(s):  
Ana CR Ribeiro ◽  
Elisa H Hawkins ◽  
Fay M Jahr ◽  
Joseph L McClay ◽  
Laxmikant S Deshpande
Keyword(s):  
Molecular Mechanisms ◽  
Low Dose ◽  
Forced Swim Test ◽  
Preference Test ◽  
Complete Recovery ◽  
Male Rats ◽  
High Dose ◽  
Adult Rats ◽  
Dose Dependent

Organophosphate (OP) chemicals include commonly used pesticides and also chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. While a chronic low-dose OP exposure does not produce acute cholinergic crises, epidemiological studies report long-term neuropsychiatric issues including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of a single, high-dose CPF or studied sub-chronic behavioral effects particularly the motor and cognitive effects of repeated low-dose CPF exposure. However, studies on chronic mood and depression-related morbidities following repeated sub-threshold CPF doses that would mimic occupationally-relevant OP exposures are lacking. Here, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21-days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following an 11-week washout period, CPF-treated rats exhibited a dose-dependent increase in signs of anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) despite a complete recovery of ChE activity at this stage. We speculate that both cholinergic and non-cholinergic mechanisms could play a role in the development of chronic OP-related depressive outcomes. The proposed CPF exposure paradigm could provide an ideal model to further study molecular mechanisms underlying cause and effect relationships between environmental OP exposures and the development of chronic behavioral deficits.

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