Interferon-β Fails to Protect in a Model of Transient Focal Stroke

Abstract

Background and Purpose-Compelling evidence supporting the role of inflammation in the development of cerebral infarction has focused attention on the potential of antiinflammatory treatment strategies for stroke. Interferon (IFN)-␤, an immunomodulatory agent approved for treatment of multiple sclerosis, is being evaluated in a phase I clinical trial in acute ischemic stroke. In the present study, we evaluated the effects of wild-type rat IFN-␤ and its pegylated counterpart (PEG-IFN-␤) in a model of focal ischemia and reperfusion. Methods-After 60 minutes of middle cerebral artery occlusion, rats (nϭ12/group) were treated with IV tail injections of 8 or 16 g of IFN-␤ in 300 L of PBS once daily for 3 or 7 days or with IV or SC injections of PEG-IFN-␤ for 1 day. The animals were assessed daily for weight and for neurological findings. Additional animals underwent complete hematology and chemistry profiles, as well as complete multiorgan necropsy studies. All of the brain tissue was evaluated for assessment of infarct areas, neutrophil infiltration, and presence of hemorrhagic transformations. Results-IFN-␤ and PEG-IFN-␤ failed to protect against experimental ischemic brain injury as assessed by histopathology and neurological outcome. Furthermore, IFN-␤ treatment was associated with significant weight loss and alterations in hematology and chemistry profiles. Key Words: inflammation Ⅲ interferon ␤ Ⅲ ischemia Ⅲ neuroprotection I nflammation plays a key role in the pathophysiology of ischemic stroke, and several antiinflammatory treatment strategies have been shown to mitigate secondary brain injury after experimental cerebral ischemia 1 . Interferon (IFN)-␤, a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for treatment of relapsingremitting multiple sclerosis Ͼ10 years ago. 2 A National Institute of Neurological Disorders and Stroke-sponsored phase I clinical trial is underway to determine the safety, tolerability profile, and optimal administration route of IFN-␤ in patients with acute ischemic stroke. The rationale for use of IFN-␤ in stroke patients comes from a limited number of animal studies in which systemic administration of IFN-␤ before or after (4 to 6 hours after) stroke onset reduced infarct volumes at 24 hours 3 and after 3 weeks of reperfusion. 4 The neuroprotective effects of IFN-␤ are associated with a reduction in neutrophil infiltration and decreased blood-brain barrier (BBB) disruption, 4 -6 as well as with the promotion of cell survival factors. 7 However, the exact mechanisms through which IFN-␤ might moderate the development of ischemic stroke remain unclear. One question is whether the drug can directly access the central nervous system, because it does not penetrate the BBB well unless the barrier is substantially compromised during the ischemic insult. To date, only 2 animal stroke models have been reported that evaluate the efficacy of IFN-␤: (1) transient (1 hour) occlusion of the middle cerebral artery (MCA) via direct placement of a microv...

Loss of IRF2BP2 in Microglia Increases Inflammation and Functional Deficits after Focal Ischemic Brain Injury

“…Although a beneficial effect of IFNβ to limit stroke injury remains controversial (Maier et al, 2006; Inacio et al, 2015; Kuo et al, 2016), IFNβ is known to limit inflammatory cytokine expression via IRF2 (Hinkerohe et al, 2005; Buttmann et al, 2007). Since there are three corepressors of IRF2, including IRF2BP2, IRF2BP1 and IRF2BPL, it was not clear whether loss of one corepressor IRF2BP2 would affect IFNβ-dependent attenuation of inflammatory cytokine activation.…”

“…However, others have failed to see this effect (Maier et al, 2006) and the therapeutic utility of IFNβ on stroke recovery remains uncertain. IFNβ inhibits inflammatory cytokine expression in co-cultures of microglia and astroglia (Hinkerohe et al, 2005), in part through IRF2 activation (Buttmann et al, 2007).…”

Lipopolysaccharide-Induced Microglial Activation and Neuroprotection against Experimental Brain Injury Is Independent of Hematogenous TLR4

“…TNF α (tumor necrosis factor α ), for example, has been shown to be necessary for LPS-mediated preconditioning (Rosenzweig et al, 2007) and injections of TNF α -neutralizing antibody into the cerebral ventricles prevented microglial cytokine production (Nadeau and Rivest, 2000). Moreover, intraventricular cytokine delivery protected the CNS from future insults, whereas intravenous injection of the same cytokines failed to reproduce LPS preconditioning when BBB integrity was preserved (Nawashiro et al, 1997; Maier et al, 2006). Taking these results together, it is plausible to hypothesize that the activation of TLR4 on the luminal surface of CNS endothelial cells results in local cytokine secretion to activate resident microglia.…”

Prevention of Postischemic Neurological Deficit by Modulating the Cerebral Cell Expression of ADP-Ribosyl Cyclase (Experimental Study)

“…До сих пор продукция и активность этого цитокина рассматривалась преимущественно с позиции патогенеза вирусных нейроинфекций [20] и лишь еди ничные публикации касались влияния интерферона на процессы электровозбудимости нейронов. В литературе есть незначительное количество данных о роли интерфе рона в ишемическом поражении центральной нервной системы, в частности, оценивается негативный характер влияния гамма интерферона при ишемическом пораже нии головного мозга и приводятся данные об отсутствии нейропротективного эффекта бета интерферона в экспе риментальной модели ишемии головного мозга [21,22]. Известно, что в различных регионах мозга экспрессиру ются рецепторы к интерферону гамма (кора, таламус, ги поталамус, ноцицептивные зоны).…”

“…Известно, что в различных регионах мозга экспрессиру ются рецепторы к интерферону гамма (кора, таламус, ги поталамус, ноцицептивные зоны). Однако, избыточная хроническая продукция интерферона гамма (вместе с фактором некроза опухолей) клетками периферической крови (в частности, при болезни Альцгеймера) коррели рует с выраженностью когнитивного дефицита, постули руется негативный характер влияния гамма интерферона при ишемическом поражении головного мозга [21][22][23][24].…”