Inhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug

Karpus, William J.; Reynolds, Nathaneal; Behanna, Heather A.; Eldik, Linda J. Van; Watterson, D. Martin

doi:10.1016/j.jneuroim.2008.06.039

Cited by 14 publications

(9 citation statements)

References 27 publications

(29 reference statements)

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“…The linkage between changes in proinflammatory cytokine levels and neurologic outcomes, revealed by the improvement in synaptic endpoints (synaptic protein levels and LTP) after attenuation of proinflammatory cytokine levels by MW-151 treatment, is consistent with previous reports of MW-151 efficacy in other rodent CNS injury models, including oligomeric Aβ-induced injury (Hu et al, 2007), kainic acid-induced seizures (Somera-Molina et al, 2007, 2009), TBI models (Lloyd et al, 2008; Chrzaszcz et al, 2010), and the EAE model of multiple sclerosis (Karpus et al, 2008). These previous studies documented that MW-151 efficacy at reducing injury-induced upregulation of proinflammatory cytokine levels was associated with a reduction in long-term neuronal injury and attenuation of hippocampal-dependent cognitive deficits.…”

Section: Discussionsupporting

confidence: 91%

“…The active pharmaceutical used for biological studies was the dihydrochloride hydrate for of the water-soluble, acidic drug. Low doses per administration were employed as noted, and are similar to those used previously for efficacy in diverse animal models of CNS diseases that involve excessive proinflammatory cytokine production as part of the pathology progression mechanism, including a model of early AD (Hu et al, 2007), TBI (Lloyd et al, 2008; Chrzaszcz et al, 2010), multiple sclerosis (Karpus et al, 2008), and seizures (Somera-Molina et al, 2007, 2009) at low doses similar to that used in this study.…”

Section: Methodsmentioning

confidence: 99%

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Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology

Bachstetter¹,

Norris²,

Sompol³

et al. 2012

Journal of Neuroscience

105

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Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer’s disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex, and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression, and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology

Bachstetter¹,

Norris²,

Sompol³

et al. 2012

Journal of Neuroscience

105

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“…The improved outcomes with Mzc administration in multiple acute or chronic injury models where proinflammatory cytokine upregulation contributes to neurologic injury (Hu et al, 2007; Somera-Molina et al, 2007; Karpus et al, 2008; Lloyd et al, 2008) suggest that disease-specific interventions may be more effective if combined with therapies that modulate glial responses. These results are additional evidence that glial activation may be a common pathophysiologic mechanism and therapeutic target in diverse forms of neurologic injury (Akiyama et al, 2000; Craft et al, 2005; Emsley et al, 2005; Hu et al, 2005; Perry et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model

Somera-Molina¹,

Nair²,

Eldik³

et al. 2009

Brain Research

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Early-life seizures result in increased susceptibility to seizures and greater neurologic injury with a second insult in adulthood. The mechanisms which link seizures in early-life to increased susceptibility to neurologic injury following a ‘second hit’ are not known. We examined the contribution of microglial activation and increased proinflammatory cytokine production to the subsequent increase in susceptibility to neurologic injury using a kainic acid (KA)-induced, established ‘two-hit’ seizure model in rats. Postnatal day (P)15 rats were administered intraperitoneal KA (early-life seizures) or saline, followed on P45 with either a ‘second hit’ of KA, a first exposure to KA (adult seizures), or saline. We measured the levels of proinflammatory cytokines (IL-1β, TNF-α, and S100B), the chemokine CCL2, microglial activation, seizure susceptibility and neuronal outcomes in adult rats 12 hours and 10 days after the second hit on P45. The ‘two-hit’ group exposed to KA on both P15 and P45 had higher levels of cytokines, greater microglial activation, and increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Treatment after early-life seizures with Minozac, a small molecule experimental therapeutic that targets up-regulated proinflammatory cytokine production, attenuated the enhanced microglial and cytokine responses, the increased susceptibility to seizures, and the greater neuronal injury in the ‘two-hit’ group. These results implicate microglial activation as one mechanism by which early-life seizures contribute to increased vulnerability to neurologic insults in adulthood, and indicate the potential longer term benefits of early-life intervention with therapies that target up-regulation of proinflammatory cytokines.

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“…We developed [ 9 ] a CNS-penetrant, small molecule experimental therapeutic, MW01-2-151WH (MW151), that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. MW151 is efficacious in a variety of animal models of diseases where proinflammatory cytokine overproduction is a component of disease progression, including (1) animal models of Alzheimer’s disease [ 9 , 10 ]; (2) neurologic sequelae of seizures [ 11 , 12 ]; (3) EAE model of multiple sclerosis [ 13 ]; (4) a ‘two-hit’ injury model of increased susceptibility to seizures after a TBI [ 14 ], and (5) radiation-induced cognitive impairment [ 15 ]. Particularly relevant to the current study, we have previously reported [ 16 ] that MW151 is efficacious in a closed head injury (CHI) model of diffuse TBI in mice, when administered during the time of the acute post-injury cytokine surge.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic

Bachstetter

Webster

Goulding

et al. 2015

J Neuroinflammation

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BackgroundEvidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test dose dependence of MW151 to suppress the target mechanism (proinflammatory cytokine up-regulation), and explore the therapeutic window for MW151 efficacy.MethodsWe examined suppression of the acute cytokine surge when MW151 was administered at different times post-injury and the dose-dependence of cytokine suppression. We also tested a more prolonged treatment with MW151 over the first 7 days post-injury and measured the effects on cognitive impairment and glial activation.ResultsMW151 administered up to 6 h post-injury suppressed the acute cytokine surge, in a dose-dependent manner. Administration of MW151 over the first 7 days post-injury rescues the CHI-induced cognitive impairment and reduces glial activation in the focus area of the CHI.ConclusionsOur results identify a clinically relevant time window post-CHI during which MW151 effectively restores cytokine production back towards normal, with a resultant attenuation of downstream cognitive impairment.

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Inhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug

Cited by 14 publications

References 27 publications

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology

Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a ‘two-hit’ seizure model

Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic

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