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Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion. PLoS One 2022; 17:e0261644. [PMID: 35015765 PMCID: PMC8752009 DOI: 10.1371/journal.pone.0261644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/07/2021] [Indexed: 11/19/2022] Open
Abstract
Background Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury. Methods C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2. Results The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01). Conclusions Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.
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Seiler A, Sood AK, Jenewein J, Fagundes CP. Can stress promote the pathophysiology of brain metastases? A critical review of biobehavioral mechanisms. Brain Behav Immun 2020; 87:860-880. [PMID: 31881262 DOI: 10.1016/j.bbi.2019.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 12/15/2019] [Accepted: 12/20/2019] [Indexed: 01/20/2023] Open
Abstract
Chronic stress can promote tumor growth and progression through immunosuppressive effects and bi-directional interactions between tumor cells and their microenvironment. β-Adrenergic receptor signaling plays a critical role in mediating stress-related effects on tumor progression. Stress-related mechanisms that modulate the dissemination of tumor cells to the brain have received scant attention. Brain metastases are highly resistant to chemotherapy and contribute considerably to morbidity and mortality in various cancers, occurring in up to 20% of patients in some cancer types. Understanding the mechanisms promoting brain metastasis could help to identify interventions that improve disease outcomes. In this review, we discuss biobehavioral, sympathetic, neuroendocrine, and immunological mechanisms by which chronic stress can impact tumor progression and metastatic dissemination to the brain. The critical role of the inflammatory tumor microenvironment in tumor progression and metastatic dissemination to the brain, and its association with stress pathways are delineated. We also discuss translational implications for biobehavioral and pharmacological interventions.
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Affiliation(s)
- Annina Seiler
- Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Josef Jenewein
- Clinic Zugersee, Center for Psychiatry and Psychotherapy, Oberwil-Zug, Switzerland
| | - Christopher P Fagundes
- Department of Psychology, Rice University, Houston, TX, United States; Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Benbenishty A, Gadrich M, Cottarelli A, Lubart A, Kain D, Amer M, Shaashua L, Glasner A, Erez N, Agalliu D, Mayo L, Ben-Eliyahu S, Blinder P. Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLoS Biol 2019; 17:e2006859. [PMID: 30921319 PMCID: PMC6469801 DOI: 10.1371/journal.pbio.2006859] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 04/17/2019] [Accepted: 02/28/2019] [Indexed: 02/07/2023] Open
Abstract
Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, is effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. Studying mechanisms underlying the therapeutic effects of CpG-C, we found that in the brain, unlike in the periphery, natural killer (NK) cells and monocytes are not involved in controlling metastasis. Next, we demonstrated that the systemically administered CpG-C is taken up by endothelial cells, astrocytes, and microglia, without affecting blood-brain barrier (BBB) integrity and tumor brain extravasation. In vitro assays pointed to microglia, but not astrocytes, as mediators of CpG- C effects through increased tumor killing and phagocytosis, mediated by direct microglia-tumor contact. In vivo, CpG-C-activated microglia displayed elevated mRNA expression levels of apoptosis-inducing and phagocytosis-related genes. Intravital imaging showed that CpG-C-activated microglia cells contact, kill, and phagocytize tumor cells in the early stages of tumor brain invasion more than nonactivated microglia. Blocking in vivo activation of microglia with minocycline, and depletion of microglia with a colony-stimulating factor 1 inhibitor, indicated that microglia mediate the antitumor effects of CpG-C. Overall, the results suggest prophylactic CpG-C treatment as a new intervention against brain metastasis, through an essential activation of microglia.
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Affiliation(s)
- Amit Benbenishty
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
- Neurobiology Department, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Meital Gadrich
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- School for Molecular Cell Biology & Biotechnology, Tel Aviv University, Tel Aviv, Israel
| | - Azzurra Cottarelli
- Department of Neurology, Columbia University Medical Center, New York, New York, United States of America
| | - Alisa Lubart
- Neurobiology Department, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - David Kain
- Neurobiology Department, Tel Aviv University, Tel Aviv, Israel
| | - Malak Amer
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lee Shaashua
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ariella Glasner
- The Lautenberg Centre for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Neta Erez
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dritan Agalliu
- Department of Neurology, Columbia University Medical Center, New York, New York, United States of America
| | - Lior Mayo
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- School for Molecular Cell Biology & Biotechnology, Tel Aviv University, Tel Aviv, Israel
| | - Shamgar Ben-Eliyahu
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Pablo Blinder
- Neurobiology Department, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br J Anaesth 2017; 120:188-196. [PMID: 29397129 DOI: 10.1016/j.bja.2017.11.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 08/04/2017] [Accepted: 09/03/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an α2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression. METHODS Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6-12 h, and its effects on metastasis formation, using various cancer types, were studied in naïve animals and in the context of stress and surgery. RESULTS Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through α2-adrenergic, but not α1-adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors. CONCLUSIONS The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.
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