Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain

Radhakrishnan, Hamsanandini; Ubele, Margo F.; Krumholz, Stephanie M.; Boaz, Kathy; Mefford, Jennifer L.; Jones, Erin Denhart; Meacham, Beverly; Smiley, Jeffrey R.; Puskás, László G.; Powell, David K.; Norris, Christopher M.; Stark, Craig E.L.; Head, Elizabeth

doi:10.1523/jneurosci.0361-21.2021

Cited by 17 publications

(9 citation statements)

References 103 publications

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“…It is also possible that the scale is not sensitive to subtle differences in cognitive function [ 36 ]. Generally, the present study indicated that MRI can detect brain damage caused by chemotherapy earlier than scales, which is consistent with previous studies [ 37 – 39 ].…”

Section: Discussionsupporting

confidence: 93%

Changes in Degree Centrality and Functional Connectivity after the First Cycle of Neoadjuvant Chemotherapy in Newly Diagnosed Breast Cancer: A Longitudinal Study

Liu

Deng

et al. 2022

Disease Markers

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Purpose. To evaluate the longitudinal changes of brain degree centrality (DC) and functional connectivity (FC) in breast cancer patients after the first cycle of neoadjuvant chemotherapy (NAC). Methods. Thirty-five breast cancer patients were included in the NAC group. Resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological test were performed at baseline before NAC (time point 0, TP0) and after the first cycle of NAC (time point 1, TP1). The healthy controls (HC) included 30 healthy subjects and received the same rs-fMRI scan and neuropsychological test as the above-mentioned NAC group at one time point. DC and FC analyses were conducted to assess brain connectivity of all participants. Receiver operating characteristic (ROC) curve was used to assess the ability of DC and FC in distinguishing patients before and after chemotherapy. Results. In the NAC group, the Self-Rating Anxiety Scale scores decreased significantly over time. At TP0 and TP1, the Digital Span Test forward score of the NAC group was significantly lower than that of the HC group. In the NAC group, DC in the right middle frontal gyrus and left precentral gyrus/middle frontal gyrus decreased significantly at TP1, and FC between the left precentral gyrus/middle frontal gyrus and bilateral precuneus was significantly reduced at TP1. Through ROC analysis, we found that the area under the curve (AUC) of DC, FC, and the combined model in distinguishing patients in TP0 or TP1 was 0.7886, 0.7665, and 0.8278, respectively. Conclusions. Brain connectivity, involving executive and motor function related brain areas, changes in the short term after NAC treatment in breast cancer patients.

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Section: Discussionsupporting

confidence: 93%

Changes in Degree Centrality and Functional Connectivity after the First Cycle of Neoadjuvant Chemotherapy in Newly Diagnosed Breast Cancer: A Longitudinal Study

Liu

Deng

et al. 2022

Disease Markers

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“…Therefore, a clinical trial of FK506 treatment in early-stage PD patients would pose no significant logistical or regulatory challenges. The established approval of FK506 for other uses, its high brain penetrance ( Murakami et al, 2004 ; Taglialatela et al, 2015 ; Radhakrishnan et al, 2021 ), and its safety profile provide a strong rationale for repurposing it against synucleinopathies.…”

Section: Discussionmentioning

confidence: 99%

Harnessing IGF-1 and IL-2 as biomarkers for calcineurin activity to tailor optimal FK506 dosage in α-synucleinopathies

Zaichick,

Caraveo

2023

Front. Mol. Biosci.

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Introduction: Rise in Calcium (Ca2+) and hyperactive Ca2+-dependent phosphatase calcineurin represent two key determinants of a-synuclein (a-syn) pathobiology implicated in Parkinson’s Disease (PD) and other neurodegenerative diseases. Calcineurin activity can be inhibited with FK506, a Food and Drug Administration (FDA)-approved compound. Our previous work demonstrated a protective effect of low doses of FK506 against a-syn pathology in various models of a-syn related pathobiology.Methods: Control and a-syn-expressing mice (12-18 months old) were injected with vehicle or two single doses of FK506 administered 4 days apart. Cerebral cortex and serum from these mice were collected and assayed using a meso scale discovery quickplex SQ 120 for cytokines and Enzyme-linked immunosorbent assay for IGF-1.Results: In this study we present evidence that reducing calcineurin activity with FK506 in a-syn transgenic mice increased insulin growth factor (IGF-1), while simultaneously decreasing IL-2 levels in both cerebral cortex and serum.Discussion: The highly conserved Ca2+/calcineurin signaling pathway is known to be affected in a-syn-dependent human disease. FK506, an already approved drug for other uses, exhibits high brain penetrance and a proven safety profile. IL-2 and IGF-1 are produced throughout life and can be measured using standard clinical methods. Our findings provide two potential biomarkers that could guide a clinical trial of FK506 in PD patients, without posing significant logistical or regulatory challenges.

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“…We showed that FK506 was able to decrease many CNS proinflammatory cytokines and reduce the numbers of active glia, reducing neuroinflammation and increasing neuronal health. Based on our and other’s preclinical data [ 99 ], we propose that FK506 is a promising FDA-approved drug for early intervention in MCI. The critical issues to be defined remain how much FK506 should be used, when it should be given to patients and what are the most appropriate biomarkers to monitor its efficacy and side effects.…”

Section: Discussionmentioning

confidence: 99%

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer’s phenotypes without blocking peripheral T cell IL-2 response

Stallings,

O’Neal,

et al. 2023

Alz Res Therapy

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Background Current treatments for Alzheimer’s disease (AD) have largely failed to yield significant therapeutic benefits. Novel approaches are desperately needed to help address this immense public health issue. Data suggests that early intervention at the first stages of mild cognitive impairment may have a greater chance for success. The calcineurin (CN)-Pin1 signaling cascade can be selectively targeted with tacrolimus (FK506), a highly specific, FDA-approved CN inhibitor used safely for > 20 years in solid organ transplant recipients. AD prevalence was significantly reduced in solid organ recipients treated with FK506. Methods Time release pellets were used to deliver constant FK506 dosage to APP/PS1 mice without deleterious manipulation or handling. Immunofluorescence, histology, molecular biology, and behavior were used to evaluate changes in AD pathology. Results FK506 can be safely and consistently delivered into juvenile APP/PS1 mice via time-release pellets to levels roughly seen in transplant patients, leading to the normalization of CN activity and reduction or elimination of AD pathologies including synapse loss, neuroinflammation, and cognitive impairment. Pin1 activity and function were rescued despite the continuing presence of high levels of transgenic Aβ42. Indicators of neuroinflammation including Iba1 positivity and IL-6 production were also reduced to normal levels. Peripheral blood mononuclear cells (PBMC) obtained during treatment or splenocytes isolated at euthanasia activated normally after mitogens. Conclusions Low-dose, constant FK506 can normalize CNS CN and Pin1 activity, suppress neuroinflammation, and attenuate AD-associated pathology without blocking peripheral IL-2 responses making repurposed FK506 a viable option for early, therapeutic intervention in AD.

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Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain

Cited by 17 publications

References 103 publications

Changes in Degree Centrality and Functional Connectivity after the First Cycle of Neoadjuvant Chemotherapy in Newly Diagnosed Breast Cancer: A Longitudinal Study

Changes in Degree Centrality and Functional Connectivity after the First Cycle of Neoadjuvant Chemotherapy in Newly Diagnosed Breast Cancer: A Longitudinal Study

Harnessing IGF-1 and IL-2 as biomarkers for calcineurin activity to tailor optimal FK506 dosage in α-synucleinopathies

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer’s phenotypes without blocking peripheral T cell IL-2 response

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