Andriessen AS, Donnelly CR, Ji RR (2021) Reciprocal interactions between osteoclasts and nociceptive sensory neurons in bone cancer pain. Pain Rep 6(1):e867. doi: 10.1097/PR9.0000000000000867
Summary: Current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. The authors discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain.
Dose: Microglial ablation using Mac1-SAP (15 μg in 8.8 μl i.t.) and Saporin control (Cat. #PR-01, 8.8 μg in 8.8 μl), is sufficient to attenuate nerve injury-induced pain in male, but not female mice. See Sorge et al. 2015.
Geraghty T, Winter DR, Miller RJ, Miller RE, Malfait AM (2021) Neuroimmune interactions and osteoarthritis pain: focus on macrophages. Pain Rep 6(1):e892. doi: 10.1097/PR9.0000000000000892
Summary: The contribution of macrophages to osteoarthritis (OA) joint damage has garnered much attention in recent years. The authors discuss how macrophages participate in the initiation and maintenance of pain in OA and provide a review of preclinical models of OA.
Dose: Using the rat monoiodoacetate-induced (MIA) model of advanced knee OA, increased microglia were observed in the ipsilateral and contralateral dorsal horn by day 7; specific ablation of spinal microglia through intrathecal injections of Mac1-SAP (15 mcg per intrathecal injection on days 0, 1, and 2), attenuated mechanical allodynia by days 5 and 7 after MIA. See Mousseau et al. 2018.
Li Y, Bao Y, Zheng H, Qin Y, Hua B (2021) Can Src protein tyrosine kinase inhibitors be combined with opioid analgesics? Src and opioid-induced tolerance, hyperalgesia and addiction. Biomed Pharmacother 139:111653. doi: 10.1016/j.biopha.2021.111653
Summary: In this review the authors discuss the important role Src protein tyrosine kinase plays in the adverse consequences of clinical application of opioids
Dose: Intrathecal injection of Mac-1-SAP depletes microglial cells in the spinal dorsal horn and alleviates the loss of anti-nociception of morphine and prevents the decrease in morphine potency. This demonstrates that spinal microglial cells are necessary for morphine tolerance (15 µg; Leduc-Pessah et al., 2017).
Li T, Zhao J, Xie W, Yuan W, Guo J, Pang S, Gan WB, Gómez-Nicola D, Zhang S (2021) Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage. J Neuroinflammation 18(1):81. doi: 10.1186/s12974-021-02127-w
Summary: The role of activated microglia during the development of ischemia remains controversial. The authors investigate the function of reactive microglia in the early stage of ischemic stroke. The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke.
Dose: Mac1-SAP is used to specifically eliminate microglia. Hippocampal slices from mouse were incubated with 13-nM Mac1-SAP for 3 to 7 days. See Montero M, Gonzalez B, Zimmer J (2009) Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration. Brain Res 1291:140-152.
Ho, IHT, Chan, MTV, Wu, WKK, Liu, X. Spinal microglia‐neuron interactions in chronic pain. (2020) J Leukoc Biol. 2020; 108: 1575-1592. doi: 10.1002/JLB.3MR0520-695R
Review: Spinal microglial activation is initiated shortly and persisted for more than 3 mo after partial sciatic nerve ligation. Intrathecal injection of Mac1-SAP, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished cold and mechanical allodynia for 2–12 wk after injury,92 supporting the role of activated microglia for chronic pain maintenance.
Cites Echeverry S, Shi XQ, Yang M, et al. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain. 2017;158(9):1792-1801.
Zhang F, Huan L, Xu T, Li G, Zheng B, Zhao H, Guo Y, Shi J, Sun J, Chen A. Inflammatory macrophages facilitate mechanical stress-induced osteogenesis. (2020) Aging (Albany NY) 12(4):3617-3625. doi: 10.18632/aging.102833
Summary: in a mouse model of distraction osteogenesis (D), there was significant increase in macrophages in the regeneration area. This suggests that targeting inflammatory macrophages may help to improve clinical bone repair.
Dose: For saporin-mediated depletion of macrophages, DO-surgery-treated mice received i.v. injection of either Mac-1-SAP against the macrophage surface marker CD11b (20µg) once every 3 days, or Rat-IgG-SAP.
Liang YJ, Feng SY, Qi YP, Li K, Jin ZR, Jing HB, Liu LY, Cai J, Xing GG, Fu KY.. Contribution of microglial reaction to increased nociceptive responses in high-fat-diet (HFD)-induced obesity in male mice. (2019) Brain Behav Immun 80:777-792. doi: 10.1016/j.bbi.2019.05.026
Saika F, Kiguchi N, Matsuzaki S, Kobayashi D, Kishioka S. Inflammatory Macrophages in the Sciatic Nerves Facilitate Neuropathic Pain Associated with Type 2 Diabetes Mellitus. (2019) J Pharmacol Exp Ther 368(3):535-544. doi: 10.1124/jpet.118.252668
Objective: To determine whether inflammatory macrophages contribute to neuropathic pain associated with type 2 diabetes-mellitus (T2DM).
Summary: Inhibitory agents for macrophage-driven neuroinflammation could be potential candidates for novel pharmacotherapy against intractable neuropathic pain.
Dose: Injections of Mac-1-SAP or unconjugated Saporin (10 μl) were administered 3 times every 2 days. Perineural administration of Mac-1-SAP improved high-fat diet (HFD)-induced mechanical allodynia and the accumulation of F4/80+ macrophages and the upregulation of inflammatory mediators in the SCN after HFD-feeding.
Ueda H. Systems Pathology of Neuropathic Pain and Fibromyalgia. (2019) Biol Pharm Bull 42(11):1773-1782. doi: 10.1248/bpb.b19-00535 (Review)
Acharjee S, Verbeek M, Gomez CD, Bisht K, Lee B, Benoit L, Sharkey KA, Benediktsson A, Tremblay M-E, & Pittman QJ. Reduced Microglial Activity and Enhanced Glutamate Transmission in the Basolateral Amygdala in Early CNS Autoimmunity. (2018). The J Neurosci, 38 (42):9019.
Objective: To identify CNS changes associated with behaviors in multiple sclerosis (MS) patients.
Summary: The data from this study reveal increased synaptic activity and spine density in early stages of experimental autoimmune encephalomyelitis (an animal model of MS) in the basolateral amygdala.
Dose: Mac-1-SAP mouse/human or Rat-IgG-SAP (control) was injected unilaterally in the BLA (1mcg/1mcl).
Lee S, Shi XQ, Fan A, West B, Zhang J. Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain (2018) Mol Pain 14:1744806918764979. doi: 10.1177/1744806918764979
Depletion of spinal microglia with selectively immunotoxin, Mac-1-SAP was able to prevent and reverse neuropathic pain behavior.
Cites: Echeverry S, Shi XQ, Yang M, Huang H, Wu Y, Lorenzo LE, Perez-Sanchez J, Bonin RP, De Koninck Y and Zhang J. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain 2017; 158: 1792–1801.)
Meng J, Ni J, Wu Z, Jiang M, Zhu A, Qing H, & Nakanishi H. The Critical Role of Il-10 in the Antineuroinflammatory and Antioxidative Effects of Rheum Tanguticum on Activated Microglia. (2018). Oxid Med Cell Longev, 2018 (Article ID 1083596):12.
Objective: To investigate anti-inflammatory and antioxidative effects of a traditional Tibetan medicine (Rheum tanguticum; RT) on activated microglia.
Summary: RT may be useful for the pharmacological intervention against excessive inflammatory and oxidative responses associated with AD by inducing the production of IL-10 by microglia.
Dose: Mac-1-SAP (1.3nM) was applied to hippocampal slice cultures 24 h prior to stimulation with chromogranin A or pancreastatin.
Mousseau M, Burma NE, Lee KY, Leduc-Pessah H, Kwok CHT, Reid AR, O’Brien M, Sagalajev B, Stratton JA, Patrick N, Stemkowski PL, Biernaskie J, Zamponi GW, Salo P, McDougall JJ, Prescott SA, Matyas JR, & Trang T. Microglial pannexin-1 channel activation is a spinal determinant of joint pain. (2018). Science Advances, 4 (8):PMID: 30101191
Objective: To identify therapeutic targets for alleviating mechnical allodynia, a sign/symptom of arthritis.
Summary: The pannexin-1 (Panx1) channel is validated as a target; blockade of P2X7 receptors or ablation of spinal microglia prevented and reversed mechanical allodynia.
Dose: Mac-1-SAP and unconjugated Saporin (15 mcg per intrathecal injection on days 0, 1, and 2). The specific depletion of spinal lumbar microglia attenuated the development of MIA-induced hypersensitivity indicating that spinal microglia causally contribute to the development of mechanical allodynia. By contrast, intrathecal injection of Control (unconjugated Saporin) did not alter the development of MIA-induced mechanical allodynia.
Burma NE, Bonin RP, Leduc-Pessah H, Baimel C, Cairncross ZF, Mousseau M, Shankara JV, Stemkowski PL, Baimoukhametova D, Bains JS, Antle MC, Zamponi GW, Cahill CM, Borgland SL, De Koninck Y, Trang T. Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents (2017) Nat Med 23:355-360. doi: 10.1038/nm.4281
Summary: The authors investigated the mechanisms underlying opiate withdrawal in rat. Depletion of spinal lumbar microglia by intrathecal injections of Mac-1–SAP (Cat. #IT-33; 20 mcg) decreased withdrawal behaviors and attenuated the severity of withdrawal without affecting morphine antinociception. Unconjugated Saporin (Cat. #PR-01; 20 mcg) was used as control and had no effect on spinal CD11b immunoreactivity or naloxone-induced morphine withdrawal.
Echeverry S, Shi XQ, Yang M, Huang H, Wu Y, Lorenzo LE, Perez-Sanchez J, Bonin RP, De Koninck Y, & Zhang J. Spinal Microglia Are Required for Long-Term Maintenance of Neuropathic Pain. (2017). Pain, 158 (9):1792-1801. 2017/07/27.
Selective depletion of spinal microglia in male rats with the targeted immunotoxin Mac-1-SAP and blockade of brain derived neurotrophic factor–TrkB signalling with intrathecal TrkB Fc chimera, but not cytokine inhibition, almost completely reversed pain hypersensitivity. To selectively deplete microglia in the spinal cord, Mac-1-SAP was injected intrathecally. In each group, rats received either an intrathecal injection of 12 mg/7 mL of Mac-1-SAP (n = 6-8) or equal volume of 0.9% saline (n 5 6) or the inactive unconjugated toxin, Saporin (n = 6).)
Leduc-Pessah H, Weilinger N, Fan C, Burma N, Thompson R, Trang T (2017) Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance. J Neurosci 37:10154-10172. doi: 10.1523/JNEUROSCI.0852-17.2017
Summary: By selectively ablating microglia in the spinal cord using a Mac-1-SAP the authors demonstrate a causal role for microglia in the development, but not maintenance, of morphine tolerance in male rats.
Dose: Mac-1-SAP or unconjugated Saporin control (15 μg) was administered by intrathecal injection.
Rosen SF, Ham B, Drouin S, Boachie N, Chabot-Dore AJ, Austin JS, Diatchenko L, Mogil JS. (2017) T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice. J Neurosci 37(41):9819-27. PMID: 28877966
Yao Y, Echeverry S, Shi XQ, Yang M, Yang QZ, Wang GY, Chambon J, Wu YC, Fu KY, De Koninck Y, Zhang J. (2016) Dynamics of spinal microglia repopulation following an acute depletion. Sci Rep 6:22839. PMID: 26961247 (Targeting Trends 16q3)
Li J, Pan Y, Zhang B, Chen Q. (2015) Macrophages are needed in the progression of tuberculosis into lung cancer. Tumour Biol 36(8):6063-6066. (Targeting Trends 15q2)
Liu W, Zhang S, Gu S, Sang L, & Dai C. Mesenchymal Stem Cells Recruit Macrophages to Alleviate Experimental Colitis through Tgfβ1. (2015). Cellular Physiology and Biochemistry, 35 (3):858-865.
Dose: For in vivo depletion of macrophages, mice received i.v. injection of Mac-1-SAP 20 µg, twice per week.
Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, Mogil JS. (2015) Different Immune Cells Mediate Mechanical Pain Hypersensitivity in Male and Female Mice. Nat Neurosci 18(8):1081-83. PMID: 26120961 (Targeting Trends 17q1)
Wang B, Miao Y, Zhao Z, Zhong Y. (2015) Inflammatory Macrophages Promotes Development of Diabetic Encephalopathy. Cell Physiol Biochem 36(3):1142-1150. (Targeting Trends 15q3)
Criscimanna A, Coudriet GM, Gittes GK, Piganelli JD, Esni F. (2014) Activated Macrophages Create Lineage-specific Microenvironments for Pancreatic Acinar- and beta-cell Regeneration in Mice. Gastroenterology 147(5):1106-1118.e11. (Targeting Trends 14q4)
Nunan R, Sivasathiaseelan H, Khan D, Zaben M, Gray W. (2014) Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release. Glia 62(8):1313-1327. (Targeting Trends 14q4)
Ferrini F, Koninck YD. (2013) Role of spinal microglia in the development of morphine-induced hyperalgesia. Targeting Trends 14(4).
Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo LE, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu JM, Cahill CM, Salter MW, De Koninck Y. (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci 16(2):183-192. (Targeting Trends 13q2)
Cusulin C, Monni E, Ahlenius H, Wood J, Brune JC, Lindvall O, & Kokaia Z. Embryonic Stem Cell-Derived Neural Stem Cells Fuse with Microglia and Mature Neurons. (2012). Stem Cells, 30 (12):2657-2671.
IT-33: Mac-1-SAP; IT-18: Mouse IgG-SAP
Summary: The fusogenic role of microglia could be even more important after NSC transplantation into brains affected by neurodegenerative diseases associated with microglia activation.
Dose: Primary Cells and NS Cell Coculture. Seven to twelve days after plating primary cells, NS cells were plated on top (10,000 cells per cm2) for 1–3 days. Rat primary cells were treated with 10 nM Mac1-SAP or Control Mouse IgG-SAP during the 5 days prior to the coculture, and analyzed 3 days thereafter.
Heldmann U, Mine Y, Kokaia Z, Ekdahl CT, Lindvall O. (2011) Selective depletion of Mac-1-expressing microglia in rat subventricular zone does not alter neurogenic response early after stroke. Exp Neurol 229(2):391-398. (Targeting Trends 11q2)
See also: Society for Neuroscience 2010 Abstracts
Montero M, Gonzalez B, Zimmer J. (2009) Depletion of Microglia by Mac-1-SAP in Mouse Hippocampal Slice Cultures Enhances Ischemia-Like Neurodegeneration. Targeting Trends 10(3).
Montero M, Gonzalez B, Zimmer J. (2009) Neuroprotective effects of the anti-inflammatory compound triflusal on ischemia-like neurodegeneration in mouse hippocampal slice cultures occur independent of microglia. Exp Neurol 218:11-23. doi: 10.1016/j.expneurol.2009.03.023
Montero M, Gonzalez B, Zimmer J (2009) Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration. Brain Res 1291:140-152. (Targeting Trends 09q4)
Domico LM, Cooper KR, Bernard LP, Zeevalk GD (2007) Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells. Neurotoxicology 28:1079-1091. (Targeting Trends 08q2)
Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ (2007) A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28(3):286-292. (Targeting Trends 07q4)
Zhao P, Waxman SG, Hains BC (2007) Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci 27:2357-2368. (Targeting Trends 07q2)
See also: Society for Neuroscience 2007 Abstracts
Kanai T, Uraushihara K, Totsuka T, Nemoto Y, Fujii R, Kawamura T, Makita S, Sawada D, Yagita H, Okumura K, Watanabe M. (2006) Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis. J Gastroenterol Hepatol 21(7):1136-1142. (Targeting Trends 06q4)
Dommergues MA, Plaisant F, Verney C, Gressens P (2003) Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience 121(3):619-628. (Targeting Trends 04q1)
Kanai T, Uraushihara K, Okazawa A, Hibi T, Watanabe M (2003) Macrophage-derived IL-18 targeting for the treatment of Crohn’s disease. Curr Drug Targets Inflamm Allergy 2(2):131-136. (Targeting Trends 04q1)
Kanai T, Watanabe M, Okazawa A, Sato T, Yamazaki M, Okamoto S, Ishii H, Totsuka T, Iiyama R, Okamoto R, Ikeda M, Kurimoto M, Takeda K, Akira S, and Hibi T (2001) Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterol 121:875-888. (Targeting Trends 02q1)