scholarly journals Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [11C]OMAR ([11C]JHU75528): Improvements in Image Quantification Using Wild-Type and Knockout Mice

2011 ◽  
Vol 10 (6) ◽  
pp. 7290.2011.00019 ◽  
Author(s):  
Raúl Herance ◽  
Santiago Rojas ◽  
Sergio Abad ◽  
Xavier Jiménez ◽  
Juan Domingo Gispert ◽  
...  
Keyword(s):  
Cb1 Receptor ◽  
New Drugs ◽  
Wild Type ◽  
Receptor System ◽  
Cannabinoid Type 1 Receptor ◽  
Positron Emission ◽  
Study Support ◽  
Genetically Manipulated ◽  
The Brain

In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [11C]OMAR ([11C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) andCB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [11C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals.

scholarly journals Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

2021 ◽  
Author(s):  
Anna Vazquez-Oliver ◽  
Silvia Perez-Garcia ◽  
Nieves Pizarro ◽  
Laura Molina-Porcel ◽  
Rafael de la Torre ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Side Effects ◽  
Mouse Model ◽  
Neurological Deficits ◽  
Wild Type ◽  
Male And Female ◽  
Cannabinoid Type 1 Receptor ◽  
Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

Neuroimaging in Alzheimer’s Disease

2013 ◽  
pp. 427-431 ◽  
Author(s):  
Hidenao Fukuyama
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Posterior Part ◽  
Lewy Body Disease ◽  
New Drugs ◽  
Amyloid Protein ◽  
Dementia Patients ◽  
Positron Emission ◽  
Occipital Lobes ◽  
The Brain

The diagnosis of Alzheimer’s disease (AD) is often based on clinical and pathological data. Positron emission tomography (PET) using the tracer 18F-FDG revealed findings specific to AD-mainly the posterior part of the brain and the association cortices of the parietal and occipital lobes were affected by a reduction in glucose metabolism. Recent advances in the development of tracers for amyloid protein, which is the key protein in the pathogenesis of AD, enables the pattern of deposition of amyloid protein in the brain to be visualized. Various tracers have been introduced to visualize other aspects of AD pathology. Recent clinical interests on dementia have focused on the early detection of AD and variation of Parkinson’s disease, namely dementia with Lewy body disease (DLB), because the earlier the diagnosis, the better the prognosis. The differential diagnosis of mild AD or mild cognitive impairment (MCI) as well as DLB has been studied using PET and MRI as part of the NIH’s Alzheimer disease Neuroimaging initiative (ADNI). At present, many countries are participating in the ADNI, which is yielding promising results. This chapter’s study will improve the development of new drugs for the treatment of dementia patients by enabling the evaluation of the effect and efficacy of those drugs.

scholarly journals Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA

2006 ◽  
Vol 80 (11) ◽  
pp. 5383-5387 ◽  
Author(s):  
Javier S. Burgos ◽  
Carlos Ramirez ◽  
Isabel Sastre ◽  
Fernando Valdivieso
Keyword(s):  
Nervous System ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Acute Infection ◽  
Wild Type ◽  
Simplex Virus ◽  
The Brain ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1) is neurotropic and enters a latent state lasting the lifetime of the host. This pathogen has recently been proposed as a risk factor for Alzheimer's disease (AD) in conjunction with apolipoprotein E4 (ApoE4). In a murine acute infection model, we showed that viral neuroinvasiveness depends directly on the overall ApoE dosage and especially on the presence of isoform ApoE4. If an interaction between ApoE and HSV-1 is involved in AD, it may occur during latency rather than during acute infection. Certainly, ApoE plays an important role in late-onset AD, i.e., at a time in life when the majority of people harbor HSV-1 in their nervous system. In the present work, wild-type, APOE knockout, APOE3, and APOE4 transgenic mice were used to analyze the influence of the ApoE profile on the levels of latent virus DNA. The knockout mice had significantly lower concentrations of the virus in the nervous system than the wild-type mice, while the APOE4 mice had very high levels in the brain compared to the APOE3 animals. ApoE4 seems to facilitate HSV-1 latency in the brain much more so than ApoE3. The APOE dosage correlated directly with the HSV-1 DNA concentration in the brain, strengthening the hypothesis that HSV-1, together with ApoE, might be involved in AD.

scholarly journals SJL/J Mice Are Highly Susceptible to Infection by Mouse Adenovirus Type 1

2001 ◽  
Vol 75 (24) ◽  
pp. 12039-12046 ◽  
Author(s):  
Katherine R. Spindler ◽  
Lei Fang ◽  
Martin L. Moore ◽  
Gwen N. Hirsch ◽  
Corrie C. Brown ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Adenovirus Type ◽  
Wild Type Virus ◽  
Mouse Strains ◽  
Wild Type ◽  
Viral Loads ◽  
Sublethal Doses ◽  
The Brain ◽  
Lethal Doses

ABSTRACT Mouse adenovirus type 1 (MAV-1) targets endothelial and monocyte/macrophage cells throughout the mouse. Depending on the strain of mouse and dose or strain of virus, infected mice may survive, become persistently infected, or die. We surveyed inbred mouse strains and found that for the majority tested the 50% lethal doses (LD50s) were >104.4 PFU. However, SJL/J mice were highly susceptible to MAV-1, with a mean LD50 of 10−0.32 PFU. Infected C3H/HeJ (resistant) and SJL/J (susceptible) mice showed only modest differences in histopathology. Susceptible mice had significantly higher viral loads in the brain and spleen at 8 days postinfection than resistant mice. Infection of primary macrophages or mouse embryo fibroblasts from SJL/J and C3H/HeJ mice gave equivalent yields of virus, suggesting that a receptor difference between strains is not responsible for the susceptibility difference. When C3H/HeJ mice were subjected to sublethal doses of gamma irradiation, they became susceptible to MAV-1, with an LD50 like that of SJL/J mice. Antiviral immunoglobulin G (IgG) levels were measured in susceptible and resistant mice infected by an early region 1A null mutant virus that is less virulent that wild-type virus. The antiviral IgG levels were high and similar in the two strains of mice. Taken together, these results suggest that immune response differences may in part account for differences in susceptibility to MAV-1 infection.

scholarly journals Distribution of Suramin, an Antitrypanosomal Drug, across the Blood-Brain and Blood-Cerebrospinal Fluid Interfaces in Wild-Type and P-Glycoprotein Transporter-Deficient Mice

2007 ◽  
Vol 51 (9) ◽  
pp. 3136-3146 ◽  
Author(s):  
Lisa Sanderson ◽  
Adil Khan ◽  
Sarah Thomas
Keyword(s):  
Choroid Plexus ◽  
Brain Perfusion ◽  
Brain Parenchyma ◽  
Sleeping Sickness ◽  
New Drugs ◽  
Wild Type ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Targeted Mutation ◽  
The Brain

ABSTRACT Although 60 million people are exposed to human African trypanosomiasis, drug companies have not been interested in developing new drugs due to the lack of financial reward. No new drugs will be available for several years. A clearer understanding of the distribution of existing drugs into the brains of sleeping sickness patients is needed if we are to use the treatments that are available more safely and effectively. This proposal addresses this issue by using established animal models. Using in situ brain perfusion and isolated incubated choroid plexus techniques, we investigated the distribution of [3H]suramin into the central nervous systems (CNSs) of male BALB/c, FVB (wild-type), and P-glycoprotein-deficient (Mdr1a/Mdr1b-targeted mutation) mice. There was no difference in the [3H]suramin distributions between the three strains of mice. [3H]suramin had a distribution similar to that of the vascular marker, [14C]sucrose, into the regions of the brain parenchyma that have a blood-brain barrier. However, the association of [3H]suramin with the circumventricular organ samples, including the choroid plexus, was higher than that of [14C]sucrose. The association of [3H]suramin with the choroid plexus was also sensitive to phenylarsine oxide, an inhibitor of endocytosis. The distribution of [3H]suramin to the brain was not affected by the presence of other antitrypanosomal drugs or the P-glycoprotein efflux transporter. Overall, the results confirm that [3H]suramin would be unlikely to treat the second or CNS stage of sleeping sickness.

scholarly journals Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1286
Author(s):  
Irene Hernández-Lozano ◽  
Severin Mairinger ◽  
Alexander Traxl ◽  
Michael Sauberer ◽  
Thomas Filip ◽  
...  
Keyword(s):  
Biliary Excretion ◽  
Drug Disposition ◽  
Functional Redundancy ◽  
Whole Body ◽  
Brain Distribution ◽  
Cancer Resistance ◽  
Wild Type ◽  
Glycoprotein P ◽  
Positron Emission ◽  
The Brain

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [11C]tariquidar, [11C]erlotinib, and [11C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice underwent dynamic whole-body PET scans after i.v. injection of either [11C]tariquidar, [11C]erlotinib, or [11C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b(−/−)Abcg2(−/−) mice than in wild-type mice, while only moderately changed in Abcb1a/b(−/−) and Abcg2(−/−) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b(−/−)Abcg2(−/−) mice and almost unchanged in Abcb1a/b(−/−) and Abcg2(−/−) mice (with the exception of [11C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2(−/−) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.

Isolated splenic sarcoidosis: a rare cause of hypercalcaemia in a patient with type 1 diabetes

2021 ◽  
Vol 14 (10) ◽  
pp. e245987
Author(s):  
Hafiz Muhammad Zubair Ullah ◽  
Ashutosh Surya ◽  
Nicholas Morley ◽  
Sajjad Ahmad
Keyword(s):  
Type 1 Diabetes ◽  
Intensive Therapy ◽  
Lymph Node Biopsy ◽  
Intensive Therapy Unit ◽  
Positron Emission Tomography Scan ◽  
Positron Emission ◽  
High Calcium ◽  
The Brain ◽  
Tomography Scan

A 30-year-old man was admitted to Intensive Therapy Unit (ITU) with status epilepticus secondary to severe hypoglycaemia on a background of type 1 diabetes. CT of the brain showed generalised cerebral oedema. He was successfully stepped down to a medical ward after 2 weeks. He was noted to have persistently high calcium, which required multiple doses of pamidronate. Parathyroid hormone level was appropriately low. CT of the thorax, abdomen and pelvis showed mild hepatosplenomegaly with small pathological lymph nodes throughout the abdomen. Bone marrow biopsy was unremarkable. Lymph node biopsy was difficult to achieve, and therefore a positron emission tomography scan was arranged. This showed an enlarged and hypermetabolic spleen. Differential diagnoses at this point included lymphoma and sarcoidosis. He underwent diagnostic splenectomy, and the diagnosis of sarcoidosis was confirmed histologically. Calcium level remained normal 17 months after splenectomy.

scholarly journals Measurement of cerebral ABCC1 transport activity in wild-type and APP/PS1-21 mice with positron emission tomography

2019 ◽  
Vol 40 (5) ◽  
pp. 954-965 ◽  
Author(s):  
Viktoria Zoufal ◽  
Severin Mairinger ◽  
Markus Krohn ◽  
Thomas Wanek ◽  
Thomas Filip ◽  
...  
Keyword(s):  
Age Groups ◽  
Brain Regions ◽  
Emission Tomography ◽  
Protective Mechanism ◽  
Transport Activity ◽  
Wild Type ◽  
Positron Emission ◽  
Amyloid Aβ ◽  
Pet Scans ◽  
The Brain

Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [11C]PiB PET scans to measure Aβ load. While baseline [11C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (kelim) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK571 pretreatment revealed significantly higher kelim values in APP/PS1-21 mice than in wild-type mice aged 170 days, suggesting increased ABCC1 activity. The observed increase in kelim occurred across all investigated brain regions and was independent of the presence of Aβ plaques measured with [11C]PiB. Western blot analysis revealed a trend towards increased whole brain ABCC1 levels in 170 days-old-APP/PS1-21 mice versus wild-type mice and a significant positive correlation between ABCC1 levels and kelim. Our data point to an upregulation of ABCC1 in APP/PS1-21 mice, which may be related to an induction of ABCC1 in astrocytes as a protective mechanism against oxidative stress.

scholarly journals Brain Distribution of Dual ABCB1/ABCG2 Substrates Is Unaltered in a Beta-Amyloidosis Mouse Model

2020 ◽  
Vol 21 (21) ◽  
pp. 8245
Author(s):  
Thomas Wanek ◽  
Viktoria Zoufal ◽  
Mirjam Brackhan ◽  
Markus Krohn ◽  
Severin Mairinger ◽  
...  
Keyword(s):  
Mouse Model ◽  
Brain Slices ◽  
Immunohistochemical Analysis ◽  
Mouse Strains ◽  
Brain Distribution ◽  
Cancer Resistance ◽  
Wild Type ◽  
Positron Emission ◽  
Pet Scans ◽  
The Brain

Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer’s disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice. Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([11C]tariquidar and [11C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [11C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [11C]erlotinib PET scans were only performed under baseline conditions. Results: Immunohistochemical analysis revealed a significant reduction (by 29–37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [11C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [11C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [11C]erlotinib. Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people.

Sign in / Sign up

Export Citation Format

Share Document