Effect of adenosine receptors on 3, 4 methylene dioxy methamphetamine induced hyperthermic, neuroinflammatory and neurotoxic effects in mouse brain

Previous studies of ours and other groups in mice have shown that 3, 4 Methylenedioxymethamphetamine (MDMA, ecstasy) produces neurotoxic damage to dopaminergic neurons and neuroinflammation and caffeine, an adenosine A1/A2A antagonist enhances glial activation induced by MDMA, suggesting potential facilitation of neurodegenerative processes. In the present study we want to investigate effect of caffeine on MDMA induced dopaminergic neurotoxicity in adult mice, whereas selective A1 ( DPCPX ) and A2A ( SCH58261 ) antagonist will be evaluated in adult mice only. C57BL/6J male mice were treated with MDMA (4x20 mg/kg, i.p.) at 2 h interval alone or in combination with caffeine (10 mg/kg, i.p.), SCH 58261( 0.5 mg/kg, i.p.), DPCPX (0.5 mg/kg, i.p.) or saline 30 mins before first and third administration of MDMA. Caffeine, SCH 58261, DPCPX was given for two more days after MDMA treatment. Mice were sacrificed 48 h after last administration of MDMA. Immunohistochemistry of tyrosine hydroxylase (TH), CD11b and glial fibrillary acidic protein (GFAP) were performed to detect dopaminergic neuronal damage, microglia and astroglia activation respectively in substantia nigra pars compacta (SNc) and striatum (CPu). Repeated administration of MDMA induced significant decrease (15%) in TH positive neurons in SNc as compare to vehicle. Association of caffeine, SCH 58261, DPCPX with MDMA did not further decrease TH positive neurons as compare to MDMA alone. MDMA induced significant increase in CD11b immunoreactivity in SNc and CPu and GFAP immunoreactivity in CPu as compare to vehicle in adult mice. Treatment with SCH 58261 significantly potentiated MDMA induced increase in CD11b immunoreactivity in both SNc and CPu, whereas SCH58261 did not alter MDMA induced GFAP immunoreactivity in CPu. In contrast, treatment with DPCPX significantly potentiated both MDMA induced increase in CD11b and GFAP immunoreactivity in CPu but not in SNc. Results suggest that association of MDMA plus caffeine could produce increase of MDMA toxicity and both A1 and A2A receptors are involved in the potentiation of MDMA-mediated neuroinflammatory but not neurodegenerative effects suggesting a role of adenosine in MDMA harmful effect

Validation of Diffusion Kurtosis Imaging as an Early-Stage Biomarker of Parkinson's Disease in Animal Models

Diffusion kurtosis imaging (DKI), which is a mathematical extension of diffusion tensor imaging (DTI), assesses non-Gaussian water diffusion in the brain. DKI proved to be effective in supporting the diagnosis of different neurodegenerative disorders. Its sensitively detects microstructural changes in the brain induced by either protein accumulation, glial cell activation or neurodegeneration as observed in mouse models of Parkinson's disease. We applied two experimental models of Parkinson's disease to validate the diagnostic utility of DKI in early and late stage of disease pathology. We present two DKI analysis methods: (1) tract based spatial statistics (TBSS), which is a hypothesis independent data driven approach intended to evaluate white matter changes; and (2) region of interest (ROI) based analysis based on hypothesis of ROIs relevant for Parkinson's disease, which is specifically used for gray matter changes. The main aim of this chapter is to provide detailed information of how to perform the DKI imaging acquisition and analysis in the mouse brain, which can be, to some extent translated to humans

Diffusion kurtosis imaging detects the time-dependent progress of pathological changes in the oral rotenone mouse model of Parkinson's disease

Clinical diagnosis of Parkinson's disease (PD) occurs typically when a substantial proportion of dopaminergic neurons in the substantia nigra (SN) already died, and the first motor symptoms appear. Therefore, tools enabling the early diagnosis of PD are essential to identify early-stage PD patients in which neuroprotective treatments could have a significant impact. Here, we test the utility and sensitivity of the diffusion kurtosis imaging (DKI) in detecting progressive microstructural changes in several brain regions of mice exposed to chronic intragastric administration of rotenone, a mouse model that mimics the spatiotemporal progression of PD-like pathology from the ENS to the SN as described by Braak's staging. Our results show that DKI, especially kurtosis, can detect the progression of pathology-associated changes throughout the CNS. Increases in mean kurtosis were first observed in the dorsal motor nucleus of the vagus (DMV) after 2 months of exposure to rotenone and before the loss of dopaminergic neurons in the SN occurred. Remarkably, we also show that limited exposure to rotenone for 2 months is enough to trigger the progression of the disease in the absence of the environmental toxin, thus suggesting that once the first pathological changes in one region appear, they can self-perpetuate and progress within the CNS. Overall, our results show that DKI can be a useful radiological marker for the early detection and monitoring of PD pathology progression in patients with the potential to improve the clinical diagnosis and the development of neuroprotective treatments. (Figure presented.). © 2021 International Society for Neurochemistr

Alpha mangostin inhibits proliferation, migration, and invasion of human breast cancer cells via STAT3 inhibition

Background: Signal Transducer and Activator of Transcription 3 (STAT3) is an identified critical protein associated with the progression of cancer. Alpha mangostin (α-M), a powerful dietary xanthone found to have anti-cancer properties against various cancers. However, the precise mechanism of its anti-cancer activity is not fully understood. Therefore, the current work hypothesized that targeting STAT3 with α-M inhibits the migration, invasion, and proliferation of breast cancer cells. Firstly, we evaluated the binding affinity of α-M/STAT3 complex using molecular dynamic simulations (MDS) and further we determined the likely underlying mechanism of STAT3 through in-vitro experiments. α-M treatment affected the levels of STAT3 phosphorylation, hnRNP-A1, PKM2, and EMT markers. α-M stimulation in breast cancer cells also resulted in suppressed migratory and invasive behaviour. More importantly, the treatment also affected the Ki67 and BrdU positive cells. In summary, we found the anti-migratory and anti-proliferative actions of α-M in breast cancer cells via STAT3 inhibition. Also, the study significantly adds a new nutraceutical for therapeutic intervention of invasive breast cancer

Caffeine Enhances Astroglia and Microglia Reactivity Induced by 3,4-Methylenedioxymethamphetamine (‘Ecstasy’) in Mouse Brain

Several reports suggest that 3,4-methylenedioxymethamphetamine (MDMA) induces neurotoxic effects and gliosis. Since recreational use of MDMA is often associated with caffeinated beverages, we investigated whether caffeine interferes with MDMA-induced astroglia and microglia activation, thus facilitating its neurotoxicity. MDMA (4 × 20 mg/kg) was acutely administered to mice alone or in combination with caffeine (10 mg/kg). CD11b and GFAP immunoreactivity were evaluated as markers of microglia and astroglia activation in the substantia nigra pars-compacta (SNc) and striatum. MDMA was associated with significantly higher CD11b and GFAP immunoreactivity in striatum, whereas only CD11b was significantly higher than vehicle in SNc. Caffeine potentiated the increase in CD11b and GFAP in the striatum but not in the SNc of MDMA-treated mice. The abuse of MDMA is a growing worldwide problem; the results of this study suggest that combination of MDMA plus caffeine by increasing glial activation might have harmful health consequence

Principles of diffusion kurtosis imaging and its role in early diagnosis of neurodegenerative disorders

Pathology of neurodegenerative diseases can be correlated with intra-neuronal as well as extracellular changes which lead to neuronal degeneration. The central nervous system (CNS) is a complex structure comprising of many biological barriers. These microstructural barriers might be affected by a variety of pathological processes. Specifically, changes in the brain tissue's microstructure affect the diffusion of water which can be assessed non invasively by diffusion weighted (DW) magnetic resonance imaging (MRI) techniques. Diffusion tensor imaging (DTI) is a diffusion MRI technique that considers diffusivity as a Gaussian process, i.e. does not account for any diffusion hindrance. However, environment of the brain tissues is characterized by a non-Gaussian diffusion. Therefore, diffusion kurtosis imaging (DKI) was developed as an extension of DTI method in order to quantify the non-Gaussian distribution of water diffusion. This technique represents a promising approach for early diagnosis of neurodegenerative diseases when the neurodegenerative process starts. Hence, the purpose of this article is to summarize the ongoing clinical and preclinical research on Parkinson's, Alzheimer's and Huntington diseases, using DKI and to discuss the role of this technique as an early stage biomarker of neurodegenerative conditions

Normal Skeletal Standardized Uptake Values Obtained from Quantitative Single-Photon Emission Computed Tomography/Computed Tomography: Time-Dependent Study on Breast Cancer Patients

Aim: To estimate the standard uptake values (SUVs) of Tc-99m methylene-diphosphonate (Tc-99m MDP) from normal skeletal sites in breast cancer patients using quantitative single-photon emission computed tomography (SPECT). Materials and Methods: A total of 60 breast cancer patients who underwent Tc-99m MDP SPECT/CT study at different postinjection acquisition times were included in this study. Based on postinjection acquisition time, patients were divided into four study groups (n_15 each), i.e. I st (2 h), II nd (3 h), III rd (4 h), and IV th (5 h). Image quantification (SUVmax and SUVmean) was performed using Q.Metrix software. Delineation of volume of interest was shaped around different bones of the skeletal system. Results: The highest normal SUVmax and SUVmean values were observed in lumber and thoracic vertebra (8.89 ± 2.26 and 2.89 ± 0.58) for Group I and in pelvis and thoracic (9.6 ± 1.32 and 3.04 ± 0.64), (10.93 ± 3.91 and 3.65 ± 0.97), (11.33 ± 2.67 and 3.65 ± 0.22) for Group II, III and IV, respectively. Lowest normal SUVmax and SUVmean values were observed in humerus and ribs (3.22 ± 0.67 and 0.97 ± 0.18), (5.16 ± 1.82 and 1.18 ± 0.16) for Group I, IV, and in humerus (3.17 ± 0.58 and 0.85 ± 0.26), (3.98 ± 1.12 and 1.04 ± 0.28) for Group II and III, respectively. Significant difference ( P < 0.05) noted in SUVmax for sternum, cervical, humerus, ribs, and pelvis with respect to time. However, significant difference ( P < 0.05) noted in SUVmean for all skeletal sites with respect to time. Conclusions: Our study shows variability in normal SUV values for different skeletal sites in breast cancer patients. Vertebral bodies and pelvis contribute highest SUV values. Time dependency of SUVs emphasizes the usefulness of routinely acquired images at the same time after Tc-99m MDP injection, especially in follow-up studies

Normal Skeletal Standardized Uptake Values Obtained from Quantitative Single-Photon Emission Computed Tomography/Computed Tomography:Time-Dependent Study on Breast Cancer Patients

AIM: To estimate the standard uptake values (SUVs) of Tc-99m methylene-diphosphonate (Tc-99m MDP) from normal skeletal sites in breast cancer patients using quantitative single-photon emission computed tomography (SPECT). MATERIALS AND METHODS: A total of 60 breast cancer patients who underwent Tc-99m MDP SPECT/CT study at different postinjection acquisition times were included in this study. Based on postinjection acquisition time, patients were divided into four study groups (n_15 each), i.e. I(st) (2 h), II(nd) (3 h), III(rd) (4 h), and IV(th) (5 h). Image quantification (SUVmax and SUVmean) was performed using Q.Metrix software. Delineation of volume of interest was shaped around different bones of the skeletal system. RESULTS: The highest normal SUVmax and SUVmean values were observed in lumber and thoracic vertebra (8.89 ± 2.26 and 2.89 ± 0.58) for Group I and in pelvis and thoracic (9.6 ± 1.32 and 3.04 ± 0.64), (10.93 ± 3.91 and 3.65 ± 0.97), (11.33 ± 2.67 and 3.65 ± 0.22) for Group II, III and IV, respectively. Lowest normal SUVmax and SUVmean values were observed in humerus and ribs (3.22 ± 0.67 and 0.97 ± 0.18), (5.16 ± 1.82 and 1.18 ± 0.16) for Group I, IV, and in humerus (3.17 ± 0.58 and 0.85 ± 0.26), (3.98 ± 1.12 and 1.04 ± 0.28) for Group II and III, respectively. Significant difference (P < 0.05) noted in SUVmax for sternum, cervical, humerus, ribs, and pelvis with respect to time. However, significant difference (P < 0.05) noted in SUVmean for all skeletal sites with respect to time. CONCLUSIONS: Our study shows variability in normal SUV values for different skeletal sites in breast cancer patients. Vertebral bodies and pelvis contribute highest SUV values. Time dependency of SUVs emphasizes the usefulness of routinely acquired images at the same time after Tc-99m MDP injection, especially in follow-up studies

Diffusion Kurtosis Imaging Detects Microstructural Changes in a Methamphetamine-Induced Mouse Model of Parkinson's Disease

Methamphetamine (METH) abuse is known to increase the risk of Parkinson's disease (PD) due to its dopaminergic neurotoxicity. This is the rationale for the METH model of PD developed by toxic METH dosing (10 mg/kg four times every 2 h) which features robust neurodegeneration and typical motor impairment in mice. In this study, we used diffusion kurtosis imaging to reveal microstructural brain changes caused by METH-induced neurodegeneration. The METH-treated mice and saline-treated controls underwent diffusion kurtosis imaging scanning using the Bruker Avance 9.4 Tesla MRI system at two time-points: 5 days and 1 month to capture both early and late changes induced by METH. At 5 days, we found a decrease in kurtosis in substantia nigra, striatum and sensorimotor cortex, which is likely to indicate loss of DAergic neurons. At 1 month, we found an increase of kurtosis in striatum and sensorimotor cortex and hippocampus, which may reflect certain recovery processes. Furthermore, we performed tract-based spatial statistics analysis in the white matter and at 1 month, we observed increased kurtosis in ventral nucleus of the lateral lemniscus and some of the lateral thalamic nuclei. No changes were present at the early stage. This study confirms the ability of diffusion kurtosis imaging to detect microstructural pathological processes in both grey and white matter in the METH model of PD. The exact mechanisms underlying the kurtosis changes remain to be elucidated but kurtosis seems to be a valuable biomarker for tracking microstructural brain changes in PD and potentially other neurodegenerative disorders

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse