Cannabinoid effects on adenylate cyclase and phosphodiesterase activities of mouse brain

1977 ◽  
Vol 55 (4) ◽  
pp. 934-942 ◽  
Author(s):  
Thomas W. Dolby ◽  
Lewis J. Kleinsmith
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Mouse Brain ◽  
Biogenic Amine ◽  
Specific Activity ◽  
Intraperitoneal Administration ◽  
The Brain

The experiments presented in this paper examine the mechanisms underlying the ability of cannabinoids to alter the in vivo levels of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) in mouse brain. It was found that changes in cyclic AMP levels are a composite result of direct actions of cannabinoids on adenylate cyclase (EC 4.6.1.1) activity and indirect actions involving the potentiation or inhibition of biogenic amine induced activity of adenylate cyclase. Furthermore, the long-term intraperitoneal administration of 1-(−)-Δ-tetrahydrocannabinol to mice produced a form of phosphodiesterase (EC 3.1.4.17) in the brain whose activity is not stimulated by Ca2+, although its basal specific activity is similar to that of control animals. In vitro, the presence of the cannabinoids caused no significant changes in activity of brain PDE at the concentrations tested. Some correlations are presented which imply that many of the observed behavioral and physiological actions of the cannabinoids in mammalian organisms may be mediated via cyclic AMP mechanisms.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

EXTH-78. WP1874, A HIGHLY POTENT UNIQUE DNA BINDING AGENT WITH ENHANCED CNS UPTAKE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi181
Author(s):  
Rafal Zielinski ◽  
Roberto Cardenas-Zuniga ◽  
Maria Poimenidou ◽  
Magdalena Remiszewski ◽  
Edd Felix ◽  
...  
Keyword(s):  
Dna Binding ◽  
Cell Lines ◽  
Water Solubility ◽  
Intraperitoneal Administration ◽  
Orthotopic Model ◽  
Biodistribution Studies ◽  
Drug Discovery Program ◽  
The Brain

Abstract As part of our drug discovery program, we have developed structure-based modular designs of unique DNA-binding agents. The approach combines DNA intercalating and DNA “minor-groove-binding” modules. We have discovered compound WP1244 that potentially binds up to 10 bp long sequences of DNA. The unique and intriguing feature of WP1244 is its high CNS uptake combined with the picomolar to low nanomolar cytotoxicity against ependymoma and glioblastoma multiforme (GBM) cell lines and demonstrated in vivo activity in the orthotopic model of GBM. To improve water solubility and develop an IV formulation, we have synthesized WP1874, a mesylate salt of WP1244, and initiated its preclinical characterization. WP1874, similarly to its parental compound, shows high cytotoxicity in ependymoma, GBM, and medulloblastoma cell lines with IC50 in low nanomolar range and it was up to 100 to 200 times more potent than doxorubicin. Interestingly, WP1874 does not appear to be cytotoxic against normal kidney cells (VeroC1008) with IC50 > 10 μM. Preliminary pharmacokinetic and biodistribution studies performed in CD-1 mice with intact brains revealed enhanced penetration of WP1874 to the brain with Cmax 1.5-fold greater than in plasma. Respectively, WP1874 Cmax in the brain was 2.3 ug/g (~2.0 μM) vs. 1.5 μg/ml (1.3 μM) in plasma. Acute toxicity in intravenously administered WP1874 was LD50 >15mg/kg. No mortalities or any apparent toxicity symptoms were recorded for six intravenous weekly doses of WP1874 at 2.5 or 5 mg/kg in CD-1, Balb/c, or nude athymic mice. Intraperitoneal administration was well-tolerated up to 5 mg/kg given three times a week for four cycles. High CNS uptake, excellent cytotoxicity against different brain cancer cell lines, and low toxicity in vivo and in vitro against normal cells warrant further investigation of WP1874 as a mechanically unique potential anticancer agent against CNS malignancies.

The influx of amino acids into the brain of the rat in vivo : the essential compared with some non-essential amino acids

1973 ◽  
Vol 183 (1070) ◽  
pp. 59-70 ◽  
Keyword(s):  
Amino Acids ◽  
Specific Activity ◽  
Essential Amino Acids ◽  
Transport Processes ◽  
Carrier Mediated Transport ◽  
A New Technique ◽  
High Degree ◽  
The Brain

The cerebral influx rates of fifteen amino acids were measured directly in living rats by means of a new technique which makes it possible to maintain a constant specific activity of a radioactively labelled amino acid in the bloodstream. A wide variation in the influx rates of the amino acids was found. These rates differed from those found by other workers using in vitro preparations, but are consistent with the theory that amino acids enter the brain mainly by carrier mediated transport processes with a high degree of specificity. There are a number of important differences between the behaviour of the transport processes in vivo and in vitro . The influx rates of the various amino acids were directly proportional to their concentra­tions in blood plasma (over the range of concentrations studied). All the nutritionally essential amino acids had relatively high influx rates as did other amino acids which the brain does not seem to be able to synthesize. On the other hand, amino acids that the brain can readily synthesize and two amino acids which are not normally found in mammalian tissues had low influx rates.

Renal cyclic AMP accumulation and adenulate cyclase stimulation by erythropoietic agents

1975 ◽  
Vol 229 (5) ◽  
pp. 1387-1392 ◽  
Author(s):  
GM Rodgers ◽  
JW Fisher ◽  
WJ George
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Regional Distribution ◽  
Renal Medulla ◽  
Iron Incorporation ◽  
Erythropoietin Production ◽  
Cyclic Amp Accumulation ◽  
Stimulation Of

The regional distribution of cyclic AMP in the kidney was determined following erythropoietic stimulation with hypoxia and cobalt. Following these stimuli, increases in renal cyclic AMP concentrations were restricted to the cortex. The basis for this localization in the case of cobalt treatment was found to reside in the stimulation of renal cortical adenylate cyclase activity in vitro by concentrations of cobalt similar to those found in vivo. The level of cobalt in the cortex after cobalt treatment was found to approach 500 mumol/kg of tissue, whereas no detectable levels of cobalt were found in the renal medulla. Additionally, other agents such as parathyroid hormone and lactic acid, that are known to lack stimulatory effects on medullary adenylate cyclase, were found to stimulate the cortical enzyme. This stimulation of renal cortical adenylate cyclase correlates with enhanced erythropoiesis as demonstrated by increased radiolabeled iron incorporation into erythrocytes. These results support previous reports which suggest that renal cortical cyclic AMP mediates erythropoietin production in response to erythropoietically active agents.

scholarly journals An argument for broad use of high efficacy treatments in early multiple sclerosis

2019 ◽  
Vol 7 (1) ◽  
pp. e636 ◽  
Author(s):  
James M. Stankiewicz ◽  
Howard L. Weiner
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Approach ◽  
Disease Course ◽  
Long Term Outcomes ◽  
The Past ◽  
Recent Developments ◽  
The Brain

Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS.

EFFECT OF HUMAN CHORIONIC GONADOTROPHIN ON ADENYLATE CYCLASE ACTIVITY AND TESTOSTERONE CONTENT IN RAT TESTICULAR MITOCHONDRIA

1977 ◽  
Vol 75 (1) ◽  
pp. 119-126 ◽  
Author(s):  
SOREL SULIMOVICI ◽  
M. S. ROGINSKY
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Dibutyryl Cyclic Amp ◽  
Trophic Hormone

The adenylate cyclase activity and the concentration of testosterone in testicular mitochondria from immature rats were measured after administration of human chorionic gonadotrophin (HCG) or dibutyryl cyclic AMP in vivo or in vitro. Intratesticular injection of HCG produced an increase in adenylate cyclase activity which preceded the rise in the level of testosterone, whereas addition of the trophic hormone in vitro resulted in simultaneous increases. Administration of dibutyryl cyclic AMP in vivo enhanced the testosterone content of the mitochondria. However, the cyclic nucleotide added in vitro at concentrations up to 5 mmol/l had no effect. Cycloheximide injected intraperitoneally before the administration of HCG abolished the stimulatory effect of the trophic hormone on the level of testosterone in the mitochondria, whereas chloramphenicol had no effect. These results, although they confirm the role of cyclic AMP as an intermediate in the stimulatory effect of HCG on the concentration of testosterone in rat testis, do not support a role for mitochondrial adenylate cyclase in this action. A protein regulator(s) formed extramitochondrially appears to be involved in the stimulatory effect of gonadotrophins on steroidogenesis.

Effects of Glucocorticoid Deficiency on Renal Medullary Cyclic Adenosine Monophosphate of Rats

1978 ◽  
Vol 54 (5) ◽  
pp. 573-577 ◽  
Author(s):  
K. Kurokawa ◽  
E. Aznar ◽  
C. Descoeudres ◽  
Anicia Zulueta ◽  
S. G. Massry
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Antidiuretic Hormone ◽  
Adenosine Monophosphate ◽  
Water Diuresis ◽  
Glucocorticoid Deficiency ◽  
Impaired Water ◽  
Adrenalectomized Rats

1. The effects of adrenalectomy on the adenylate cyclase—adenosine 3′:5′-cyclic monophosphate (cyclic AMP) system of rat renal medulla were examined to evaluate the mechanism of the impaired water diuresis in glucocorticoid deficiency. 2. Concentrations of cyclic AMP in medullary tubules from adrenalectomized rats were significantly higher than in the tubules from control animals both in the presence and absence of antidiuretic hormone. 3. This abnormality was corrected by the treatment in vivo of the adrenalectomized rats with dexamethasone, but addition of this drug to the incubation medium did not abolish the differences in cyclic AMP between tubules from adrenalectomized and normal rats. 4. The activity of adenylate cyclase or cyclic AMP phosphodiesterase in vitro was not affected by adrenalectomy. 5. In glucocorticoid deficiency, the concentration of cyclic AMP in medullary tubules is increased both with and without antidiuretic hormone. This abnormality may render medullary tubules more permeable to water and may underlie the impaired water diuresis in glucocorticoid deficiency.

scholarly journals Azole Heteroresistance in Cryptococcus neoformans: Emergence of Resistant Clones with Chromosomal Disomy in the Mouse Brain during Fluconazole Treatment

2013 ◽  
Vol 57 (10) ◽  
pp. 5127-5130 ◽  
Author(s):  
Edward Sionov ◽  
Yun C. Chang ◽  
Kyung J. Kwon-Chung
Keyword(s):  
Mouse Model ◽  
Cryptococcus Neoformans ◽  
Mouse Brain ◽  
Content Type ◽  
The Brain ◽  
Strain Dependent ◽  
Is Strain

ABSTRACTWe have previously reported thatCryptococcus neoformansstrains are innately heteroresistant to fluconazolein vitro, producing minor, highly resistant subpopulations due to adaptive formation of disomic chromosomes. Using a mouse model, we assessed the emergence of heteroresistant clones in the brain during fluconazole treatment and found that the occurrence of heteroresistant clonesin vivowith chromosomal disomy is strain dependent. Interestingly, emergence of heteroresistant clonesin vivowas unrelated to the strain's MIC to fluconazole.

scholarly journals A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

2020 ◽  
Author(s):  
Changpeng Wang ◽  
Siwei Zhang ◽  
Yuefei Zou ◽  
Hongzhao Ma ◽  
Donglang Jiang ◽  
...  
Keyword(s):  
High Performance ◽  
Specific Activity ◽  
High Accumulation ◽  
Metabolic Kinetics ◽  
Thiamine Metabolism ◽  
Pet Tracer ◽  
The Status ◽  
The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity, radiochemical purity, radiochemical concentration, were evaluated by high performance liquid chromatography (HPLC). Metabolic kinetics and brain level of 18F-deoxy-thiamine in mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency by thiamine-deprived diet (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = -0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

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