Selective accumulation of monoclonal antibodies against neurospecific enolase in brain tissue of rats with middle cerebral artery occlusion

Chekhonin, V. P.; Лебедев, С. В.; Ryabukhin, I. A.; Петров, С. В.; Gurina, O. I.; Dmitrieva, T. B.; Volkov, A. I.; Kashparov, I. A.; Skoblov, Yu. S.

doi:10.1007/s10517-005-0037-4

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…Our data show a reduced postischemic neuronal death in vivo by TLR2 inhibition in a standard experimental stroke model. We applied TLR2-blocking antibody after MCAO to mimic a potential therapeutical use and because of speculated postischemic breakdown of the blood-brain barrier (Belayev et al, 1996), which should improve the ability of the antibodies to reach their target cells (most probably macrophages/monocytes and microglia), as shown in a rat MCAO model (Chekhonin et al, 2004). The relative large variability in the stroke volumes obtained in knockout mice compared with wild-type mice ( Figure 1A) suits similar findings in other knockout mice (Harhausen et al, 2010;Trendelenburg et al, 2002;Ziegler et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…The same antibody was used to block TLR2-mediated activation of monocytes by Pneumocystis murina in vitro (Zhang et al, 2006). Recently, it was shown that intravascular applied monoclonal antibodies permeate rodent brain after induction of focal cerebral ischemia (Chekhonin et al, 2004). However, there is no information about therapeutical use of TLR2 inhibitors in cerebral ischemia in vivo up to now.…”

Section: Introductionmentioning

confidence: 99%

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Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke

Ziegler

Freyer

Harhausen

et al. 2010

J Cereb Blood Flow Metab

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Reduced infarct volume in TLR2-knockout mice compared with C57Bl/6 wild-type mice has recently been shown in experimental stroke and confirmed in this study. We now also show a significant decrease of CD11b-positive cell counts and decreased neuronal death in the ischemic hemispheres of TLR2-deficient mice compared with C57Bl/6wt mice 2 days after transient focal cerebral ischemia. To examine the potential benefit of intravascular TLR2 inhibition, C57Bl/6wt mice were treated intraarterially with TLR2-blocking anti-TLR2 antibody (clone T2.5) after 45 minutes of cerebral ischemia and compared with control antibody (isotype) treated wild-type mice. Whereas T2.5-treated mice had no reduction in infarct volumes at 48 hours after reperfusion, they did have decreased numbers of CD11b-positive inflammatory cells and decreased neuronal death compared with isotype-treated control mice. Comparison of the isotype antibody treatment to control (saline) treatment showed no effects on infarct volumes or neuronal survival. However, mice treated with the control isotype antibody had increased numbers of CD11b-positive inflammatory cells compared with saline-treated animals. Thus, antibody treatment itself (i.e., control isotype antibody, but potentially of any antibody) may have adverse effects and limit therapeutic benefit of anti-TLR2-antibody therapy. We conclude that TLR2 mediates leukocyte and microglial infiltration and neuronal death, which can be attenuated by TLR2 inhibition. The TLR2 inhibition in vivo improves neuronal survival and may represent a future stroke therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke

Ziegler

Freyer

Harhausen

et al. 2010

J Cereb Blood Flow Metab

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“…TLR4 defective mice were shown to be protective against ischemic stroke in several investigations [ 107 , 108 , 109 , 110 ]. Following the establishment of localized cerebral ischemia, intravascularly administered monoclonal antibodies penetrate the rodent brain [ 111 ]. The anti-inflammatory impact of TLR4-inhibition in experimental stroke was specifically established by the administration of TLR4 blocking antibody (mAbs clone MTS510) in vivo [ 112 ] ( Table 2 ).…”

Section: Application Of Antibody-based Drugs For Cerebral Ischemiamentioning

confidence: 99%

Advances in Antibody-Based Therapeutics for Cerebral Ischemia

et al. 2022

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Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood–brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.

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Evaluation of the Therapeutic Potential of Anti-TLR4-Antibody MTS510 in Experimental Stroke and Significance of Different Routes of Application

et al. 2016

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Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged.

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Selective accumulation of monoclonal antibodies against neurospecific enolase in brain tissue of rats with middle cerebral artery occlusion

Cited by 3 publications

References 7 publications

Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke

Blocking TLR2 in vivo Protects against Accumulation of Inflammatory Cells and Neuronal Injury in Experimental Stroke

Advances in Antibody-Based Therapeutics for Cerebral Ischemia

Evaluation of the Therapeutic Potential of Anti-TLR4-Antibody MTS510 in Experimental Stroke and Significance of Different Routes of Application

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