Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

BACKGROUND: The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. METHODS: Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. RESULTS: MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. CONCLUSION: Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

An enigma of hypothyroidism and hyponatremia coexistence: a nationwide population-based retrospective study.

INTRODUCTION: Hypothyroidism is a rare and possible cause of hyponatremia. However, the clinical epidemiology and risk of mortality (ROM) when they coexist still remain elusive. OBJECTIVES: We assessed the epidemiology and ROM among index patients with coexisting hypothyroidism and hyponatremia via a national population database. PATIENTS AND METHODS: This retrospective cohort study utilized Taiwan's National Health Insurance program database. Distributions of definite sociodemographic factors were analyzed. The annual incidence among the overall group and sex-subgroups was investigated. In addition, potential factors influencing the ROM were also evaluated. RESULTS: Of 4,549,226 patients from 1998 to 2015, a total of 3,140 index patients with concurrent hypothyroidism and hyponatremia were analyzed. The incidence rate increased tenfold from 1998 to 2015; average annual incidence rate was 174. Among the total participants, 57.1% were women; mean age was 72.6 ± 14.7 years and 88.8% were aged > 55 years. Although average length of stay (LOS) was 13.1 ± 15.4 days, the mortality group had significantly longer LOS than that in the survival group (12.9 days vs 22.2 days). Old age, catastrophic illness, cardiac dysrhythmia, and low hospital hierarchy were independent predictors of hospital mortality. The optimal LOS cutoff value for ROM prediction was 16 days. Index patients with LOS > 16 days increased ROM by 2.3-fold. CONCLUSIONS: Coexistent hypothyroidism and hyponatremia is rare, although the incidence increased gradually. Factors influencing the ROM, such as old age, underlying catastrophic status, cardiac dysrhythmia, hospital hierarchy, and LOS should be considered in clinical care.

Assessment of the anti-nociceptive effects of fetal ventral mesencephalic tissue allografts in a rat model of hemi-Parkinson's disease using fMRI.

Extensive studies showed increased subjective pain sensitivity in Parkinson's disease (PD), which appeared to be partially reversed by dopaminergic (DA) treatment. Although cell replacement represents an attractive therapeutic strategy, its potential for PD-related hyperalgesia remains unclear. We investigated re-establishment of DA function via allografting exogenic DA cells on pain hypersensitivity in a rat model of PD. We evaluated the anti-nociceptive effects of fetal ventral mesencephalic (rVM) tissue allografts in PD rats after unilateral 6-OHDA-induced toxicity in the medial forebrain bundle. The drug -induced rotation test was used to validate the severity of the nigrostriatal lesion; von Frey and thermal pain tests were employed to evaluate nociceptive function. Nociception-induced cerebral blood volume (CBV) response was measured using a 4.7-T MR system. Finally, the immunohistochemical (IHC) studies were performed and the results were compared with the imaging findings from functional magnetic resonance imaging (fMRI). The grafts significantly improved drug-induced rotation behavior and increased mechanical and thermal nociceptive thresholds in PD rats. The elevation of CBV signals significantly recovered on the grafted striatum, whereas this effect was inhibited by the D2R antagonist eticlopride in each striatum. Quantitative IHC analysis revealed the transplantation markedly increased the numbers of tyrosine hydroxylase immunoreactive cells. Therefore, we concluded transplantation of rVM tissue results in anti-nociceptive effects and improves motor function. Moreover, in vivo CBV response confirmed the key role of D2R-mediated pain modulation. Therefore, we demonstrate fMRI as a reliable imaging index in evaluating the anti-nociceptive therapeutic effects of fetal rVM transplantation in the rat model of PD.

Preliminary Results on the Long-Term Effects of Dextromethorphan on MDMA-Mediated Serotonergic Deficiency and Volumetric Changes in Primates Based on 4-[18F]-ADAM PET/MRI.

Alterations to the serotonergic system due to 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) consumption have been extensively documented. However, knowledge of the reversibility of these neurotoxic effects based on in vivo evaluations of serotonin transport (SERT) availability remains limited. This study aimed to evaluate the long-term neurotoxicity of MDMA after 66 months abstinence and explored whether Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor, could attenuate MDMA-induced neurotoxicity using 4-[18F]-ADAM, an imaging ligand that selectively targets SERT, with positron emission tomography technology (PET). Nine monkeys (Macaca cyclopis) were used in this study: control, MDMA, and DM + MDMA. Static 4-[18F]-ADAM PET was performed at 60 and 66 months after drug treatment. Serotonin transport (SERT) availability was presented as the specific uptake ratios (SURs) of 4-[18F]-ADAM in brain regions. Voxel-based region-specific SERT availability was calculated to generate 3D PET/MR images. Structural Magnetic Resonance Imaging (MRI) volumetric analysis was also conducted at 60 months. Significantly decreased 4-[18F]-ADAM SURs were observed in the striatum and thalamus of the MDMA group at 60 and 66 months compared to controls; the midbrain and frontal cortex SURs were similar at 60 and 66 months in the MDMA and control groups. All eleven brain regions showed significantly lower (∼13%) self-recovery rates over time; the occipital cortex and cingulate recovered to baseline by 66 months. DM attenuated MDMA-induced SERT deficiency on average, by ∼8 and ∼1% at 60 and 66 months, respectively; whereas significant differences were observed between the thalamus and amygdala of the MDMA and DM + MDMA groups at 66 months. Compared to controls, the MDMA group exhibited significantly increased (∼6.6%) gray matter volumes in the frontal cortex, occipital cortex, caudate nucleus, hippocampus, midbrain, and amygdala. Moreover, the gray matter volumes of the occipital cortex, hippocampus and amygdala correlated negatively with the 4-[18F]-ADAM SURs of the same regions. DM (n = 2) did not appear to affect MDMA-induced volumetric changes. The 4-[18F]-ADAM SURs, lower self-recovery rate and increased volumetric values indicate the occipital cortex, hippocampus and amygdala still exhibit MDMA-induced neurotoxicity after 66 months' abstinence. Moreover, DM may prevent MDMA-induced serotonergic deficiency, as indicated by increased 4-[18F]-ADAM SURs and SERT availability, but not volumetric changes.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

Radioactive Iodine Treatment for Thyroid Cancer Patients Increases the Risk of Long-Term Gastrointestinal Disorders: A Nationwide Population-Based Cohort Analysis.

(1) Background: The study aimed to investigate the association between radioactive iodine (RAI) treatment and long-term gastrointestinal disorders including ulcers, atrophic gastritis, and secondary malignant neoplasm of the stomach in patients with thyroid cancer. (2) Methods: The data of the study were extracted from the National Health Insurance Database (NHIRD) of Taiwan between 2000 to 2015. Patients of ages older than 20 with thyroid cancer after thyroidectomy were included and divided into groups with RAI (study cohort) and without RAI (comparison cohort). Multivariate Cox proportional hazards regression analysis and the Kaplan-Meier method were used for statistical analysis. (3) Results: A total of 7250 (with RAI: 5800, without RAI: 1450) patients were included. The Kaplan-Meier analysis revealed a significantly higher cumulative risk for overall gastrointestinal disorders in the group with RAI (log-rank p = 0.034). The risk for gastrointestinal disorders was higher when receiving a cumulative RAI dose higher than 1.11 GBq in the Cox regression analysis. In the subgroup analysis, the risks of gastric and duodenal ulcers are significantly higher in the group with RAI treatment. (4) Conclusions: This study revealed that RAI was associated with an increased risk for long-term gastrointestinal disorders, specifically gastric and duodenal ulcers, in thyroid cancer, especially when the cumulative dose exceeds 1.11 GBq.

Bezafibrate Exerts Neuroprotective Effects in a Rat Model of Sporadic Alzheimer's Disease.

Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, reportedly attenuated tau pathology in a transgenic mouse model of primary tauopathy. Since tau pathology is a neuropathological hallmark of Alzheimer's disease (AD), bezafibrate may be a potential drug for the treatment of AD. However, no study has investigated its effects in AD models. Thus, we aimed to evaluate whether bezafibrate has neuroprotective effects in a sporadic AD model induced by streptozotocin (STZ) intracerebroventricular (ICV) injection. Rats were administered STZ-ICV (3 mg/kg) followed by bezafibrate (50 mg/kg/day, intraperitoneal) for 4 weeks. Behavior tests and positron emission tomography (PET) were performed to evaluate longitudinal changes in cognitive function, tau pathology, and cerebral glucose metabolism. Immunofluorescence staining was performed to assess neuronal survival and microglial accumulation. STZ-ICV administration induced significant cognitive impairment and substantial neuronal loss, tau pathology, glucose hypometabolism, and microgliosis in the cortex and hippocampus, while bezafibrate effectively attenuated these abnormalities. This study demonstrated that bezafibrate has long-lasting neuroprotective effects in a sporadic AD model. Our data indicate that the neuroprotective effects of bezafibrate might be associated with its ability to ameliorate tau pathology, brain glucose hypometabolism, and neuroinflammation. These findings suggest that bezafibrate is a potential multi-target drug candidate for the treatment of AD.

Pulsed Radiofrequency Upregulates Serotonin Transporters and Alleviates Neuropathic Pain-Induced Depression in a Spared Nerve Injury Rat Model.

Neuropathic pain (NP) is difficult to treat due to complex pathophysiological mechanisms. Pulsed radiofrequency (RRF) has been used widely with neuromodulation effect in refractory chronic pain treatment. A recent study found that PRF treatment may decrease chronic pain-related anxiety-depressant symptoms in patients, even though the mechanisms are unclear. Additionally, accumulated evidence has shown serotonin uptake is correlated with various neuropsychiatric diseases. Therefore, we investigated the effects and underlying mechanisms of PRF on depression-like behaviors, resulting from spared nerve injury (SNI)-induced NP. We examined the indexes of mechanical allodynia, cold allodynia, depression-like behavior, and blood cytokines by dynamic plantar aesthesiometry, acetone spray test, forced swimming test, and ProcartaPlex multiplex immunoassays in male Wistar rats, respectively. Serotonin transporters (SERTs) in rat brains were examined by using 4-[18F]-ADAM/PET imaging. We found that specific uptake ratios (SURs) of SERTs were significantly decreased in the brain regions of the thalamus and striatum in rats with SNI-induced NP and depression-like behaviors. Additionally, the decrease in SERT density was correlated with the development of a depression-like behavior indicated by the forced swimming test results and pronounced IL-6 cytokines. Moreover, we demonstrated that PRF application could modulate the descending serotoninergic pathway to relieve pain and depression behaviors.

Radioactive Iodine Treatment and the Risk of Long-Term Cardiovascular Morbidity and Mortality in Thyroid Cancer Patients: A Nationwide Cohort Study.

(1) Background: This study aimed to investigate the association between radioactive iodine (RAI) and long-term cardiovascular disease (CVD) morbidity/mortality in thyroid cancer. (2) Methods: The study was conducted using data from the Taiwan National Health Insurance Database during 2000-2015. Thyroid cancer patients aged ≥20 years were categorized into RAI (thyroidectomy with RAI) and non-RAI (thyroidectomy only) groups. The Cox proportional hazard regression model and Kaplan-Meier method were used for analysis. (3) Results: A total of 13,310 patients were included. Kaplan-Meier analysis demonstrated that the two groups had similar cumulative risks of CVD (log-rank p = 0.72) and CVD-specific mortality (log-rank p = 0.62). On Cox regression analysis of different RAI doses, the risk of CVD was higher in the cumulative dosage >3.7 GBq (hazard ratio = 1.69, 95% confidence interval = 1.24-2.40, p < 0.001). (4) Conclusions: RAI was not associated with an increased risk of CVD in thyroid cancer. However, CVD surveillance is indicated in the patients receiving the cumulative RAI dosage above 3.7 GBq.

Association between Trichomonas vaginalis infection and cervical lesions: a population-based, nested case-control study in Taiwan.

Trichomonas vaginalis is the most common nonviral sexually transmitted infection. According to the 2019 WHO cancer report, cervical cancer is the fourth most frequent cancer in women. However, previous research, which has not included a large-scale study to date, has revealed that Trichomonas vaginalis increases cervical cancer risk. In this study, we investigated a group of Asian females in Taiwan to determine the association between trichomoniasis and the risk of developing cervical lesions, including cancer, neoplasm, and dysplasia. We conducted a nested case-control study by using the National Health Insurance (NHI) program database in Taiwan. The International Classification of Diseases, 9th Revision classifications (ICD-9-CM) was used to categorize all of the medical conditions for each patient in the case and control groups. The adjusted odds ratio (AOR) and 95% confidence interval (CI) for the association between trichomoniasis and cervical lesions were estimated using multivariable conditional logistic regression to adjust for all comorbidities and variables. In total, 54,003 individuals were enrolled in the case group and 216,012 were enrolled in the control group. Trichomonas vaginalis exposure had a significant association with cervical lesions (AOR 2.656, 95% CI = 1.411-5.353, p = 0.003), especially cervical cancer (AOR 3.684, 95% CI = 1.622-6.094, p = 0.001). In patients with both trichomoniasis and depression, the relative risk increased 7.480-fold compared to those without trichomoniasis or depression. In conclusion, female patients with Trichomonas vaginalis exposure had a significantly higher risk of developing cervical lesions (especially cervical cancer) than those without exposure.

Pilot study of a longitudinal integrated disaster and military medicine education program for undergraduate medical students.

Disaster medicine education in medical curricula is scarce and frequently nonexistent. It is reasonable to initiate educational approaches for physicians in this field at the medical school level. An understanding of disaster medicine and the health care system during massive casualty incidents has been recommended as an integral part of the medical curriculum in the United States and Germany.The goal of the reformed curriculum was to develop a longitudinal integrated disaster and military medicine education program extending from the first year to the sixth year based on previously separated clinical and military medicine topics. Emergency medicine physicians, military emergency medical technicians, and Tactical Combat Casualty Care instructors formed an interprofessional faculty group and designed a learning curriculum.A total of 230 medical students participated in the revised disaster preparedness curriculum. Satisfaction survey response rates were high (201/230, 87.4%). Most of the free-text comments on the program were highly appreciative. The students considered the number of teaching hours for the whole program to be adequate. The students showed significant improvements in knowledge and judgment regarding disaster medicine after the program.We found that medical students were highly interested, were appreciative of, and actively participated in this longitudinal integrated disaster and military medicine education program, but gaps existed between the students' scores and the educators' expectations. The educators believed that the students needed more disaster preparedness knowledge and skills.

Taking Sleeping Pills and the Risk of Chronic Kidney Disease: A Nationwide Population-Based Retrospective Cohort Study.

Background: Sleeping disorder has been associated with chronic kidney disease (CKD); however, the correlation between sleeping pills use and CKD has not been investigated in-depth yet. This study elucidated the potential association of sleeping pill use with the risk of CKD and CKD progression to end-stage renal disease (ESRD) requiring dialysis. Methods: This study was based on a population-based cohort that included 209,755 sleeping pill users among 989,753 individuals. After applying the exclusion criteria, 186,654 sleeping pill users and 373,308 nonusers were enrolled to monitor the occurrence of CKD. Using a cumulative daily dose, we analyzed the types of sleeping pills related to the risk of CKD and ESRD. Propensity score matching and analysis using Cox proportional hazards regression were performed with adjustments for sex, age, and comorbidities. Results: Sleeping pill use was related to increased CKD risk after adjusting for underlying comorbidities (adjusted hazard ratio [aHR] = 1.806, 95% confidence interval [CI]: 1.617-2.105, p < 0.001). With the exception of hyperlipidemia, most comorbidities correlated with an increased risk of CKD. Persistent use of sleeping pills after CKD diagnosis increased the risk of concurrent ESRD (aHR = 7.542; 95% CI: 4.267-10.156; p < 0.001). After the subgroup analysis for sleeping pill use, brotizolam (p = 0.046), chlordiazepoxide (p < 0.001), clonazepam (p < 0.001), diazepam (p < 0.001), dormicum (p < 0.001), estazolam (p < 0.001), fludiazepam (p < 0.001), flunitrazepam (p < 0.001), nitrazepam (p < 0.001), trazodone (p < 0.001), zolpidem (p < 0.001), and zopiclone (p < 0.001) were found to have significant correlation with increased CKD risk. Conclusion: Sleeping pill use was related to an increased risk of CKD and ESRD. Further studies are necessary to corroborate these findings.

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population-based, cohort study in Taiwan.

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Olfactory ensheathing cells improve the survival of porcine neural xenografts in a Parkinsonian rat model.

BACKGROUND: Parkinson's disease (PD) features the motor control deficits resulting from irreversible, progressive degeneration of dopaminergic (DA) neurons of the nigrostriatal pathway. Although intracerebral transplantation of human fetal ventral mesencephalon (hfVM) has been proven effective at reviving DA function in the PD patients, this treatment is clinically limited by availability of hfVM and the related ethical issues. Homologous tissues to hfVM, such as porcine fetal ventral mesencephalon (pfVM) thus present a strong clinical potential if immune response following xenotransplantation could be tamed. Olfactory ensheathing cells (OECs) are glial cells showing immunomodulatory properties. It is unclear but intriuging whether these properties can be applied to reducing immune response following neural xenotransplantation of PD. METHODS: To determine whether OECs may benefit neural xenografts for PD, different compositions of grafting cells were transplanted into striatum of the PD model rats. We used apomorphine-induced rotational behavior to evaluate effectiveness of the neural grafts on reviving DA function. Immunohistochemistry was applied to investigate the effect of OECs on the survival of neuroxenografts and underlying mechanisms of this effect. RESULTS: Four weeks following the xenotransplantation, we found that the PD rats receiving pfVM + OECs co-graft exhibited a better improvement in apomorphine-induced rotational behavior compared with those receiving only pfVM cells. This result can be explained by higher survival of DA neurons (tyrosine hydroxylase immunoreactivity) in grafted striatum of pfVM + OECs group. Furthermore, pfVM + OECs group has less immune response (CD3+ T cells and OX-6+ microglia) around the grafted area compared with pfVM only group. These results suggest that OECs may enhance the survival of the striatal xenografts via dampening the immune response at the grafted sites. CONCLUSIONS: Using allogeneic OECs as a co-graft material for xenogeneic neural grafts could be a feasible therapeutic strategy to enhance results and applicability of the cell replacement therapy for PD.

The Effect of Sertoli Cells on Xenotransplantation and Allotransplantation of Ventral Mesencephalic Tissue in a Rat Model of Parkinson's Disease.

Intra-striatal transplantation of fetal ventral mesencephalic (VM) tissue has a therapeutic effect on patients with Parkinson's disease (PD). Sertoli cells (SCs) possess immune-modulatory properties that benefit transplantation. We hypothesized that co-graft of SCs with VM tissue can attenuate rejection. Hemi-parkinsonian rats were generated by injecting 6-hydroxydopamine into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats or pigs (rVM or pVM), with/without a co-graft of SCs (rVM+SCs or pVM+SCs). Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small animal-positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. Immunohistochemistry (IHC) examination was used to determine the survival of the grafted dopaminergic neurons in the striatum and to investigate immune-modulatory effects of SCs. The results showed that the rVM+SCs and pVM+SCs groups had significantly improved drug-induced rotational behavior compared with the VM alone groups. PET revealed a significant increase in specific uptake ratios (SURs) of [18F] DOPA and [18F] FE-PE2I in the grafted striatum of the rVM+SCs and pVM+SCs groups as compared to that of the rVM and pVM groups. SC and VM tissue co-graft led to better dopaminergic (DA) cell survival. The co-grafted groups exhibited lower populations of T-cells and activated microglia compared to the groups without SCs. Our results suggest that co-graft of SCs benefit both xeno- and allo-transplantation of VM tissue in a PD rat model. Use of SCs enhanced the survival of the grafted dopaminergic neurons and improved functional recovery. The enhancement may in part be attributable to the immune-modulatory properties of SCs. In addition, [18F]DOPA and [18F]FE-PE2I coupled with PET may provide a feasible method for in vivo evaluation of the functional integrity of the grafted DA cell in parkinsonian rats.

The effect of dextromethorphan use in Parkinson's disease: A 6-hydroxydopamine rat model and population-based study.

This study investigated the effect of dextromethorphan (DXM) against Parkinson's disease (PD) in rats and explored the association between DXM dose and PD risk in elderly patients 65 years and older using a population-based database. The PD rat model (Sprague Dawley rats) was induced by injecting 6-hydroxydopamine (6-OHDA) into the unilateral medial forebrain bundle of the rat brain. DXM (20 mg/kg) was administered intraperitoneally twice daily from 7 days before the appearance of a 6-OHDA lesion to 28 days after the lesion appeared. The availability of dopamine transporter (DAT) and serotonin transporter (SERT) in the striatum of the rat brain was measured using positron emission tomography. The apomorphine-induced rotation test was performed to study the hypersensitivity of the brain regions with lesions. This animal study demonstrated that DXM significantly attenuated 6-OHDA-induced DAT and SERT loss, correlating to rotational behaviors. The population-based human study analyzed the data from the Taiwan Longitudinal Health Insurance Database 2005 between January 2005 and December 2013 and then used the DXM dose-response curve to investigate the trend of its protective effect against PD. In the human study, low cumulative doses of DXM may potentially achieve a protective effect for PD; however, high cumulative doses seem to be a risk for PD.

An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans.

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/µmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 µSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) µSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

KA-bridged transplantation of mesencephalic tissue and olfactory ensheathing cells in a Parkinsonian rat model.

The pathology of Parkinson's disease (PD) results mainly from nigrostriatal pathway damage. Unfortunately, commonly used PD therapies do not repair the disconnected circuitry. It has been reported that using kainic acid (KA, an excitatory amino acid) in bridging transplantation may be useful to generate an artificial tract and reconstruct the nigrostriatal pathway in 6-hydroxydopamine (6-OHDA) lesioned rats. In this study, we used KA bridging and a co-graft of rat olfactory ensheathing cells (OECs) and rat E14 embryonic ventral mesencephalic (VM) tissue to restore the nigrostriatal pathway of the PD model rats. The methamphetamine-induced rotational behaviour, 4-[18 F]-ADAM (a selectively serotonin transporter radioligand)/micro-PET imaging, and immunohistochemistry were used to assess the effects of the transplantation. At 9 weeks post-grafting in PD model rats, the results showed that the PD rats undergoing VM tissue and OECs co-grafts (VM-OECs) exhibited better motor recovery compared to the rats receiving VM tissue transplantation only. The striatal uptake of 4-[18 F]-ADAM and tyrosine hydroxylase immunoreactivity (TH-ir) of the grafted area in the VM-OECs group were also more improved than those of the VM alone group. These results suggested that OECs may enhance the survival of the grafted VM tissue and facilitate the recovery of motor function after VM transplantation. Moreover, OECs possibly promote the elongation of dopaminergic and serotonergic axon in the bridging graft. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT.

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.