TT-301 Inhibits Microglial Activation and Improves Outcome after Central Nervous System Injury in Adult Mice

James, Michael L.; Wang, Haichen; Cantillana, Viviana; Lei, Beilei; Kernagis, Dawn; Dawson, Hana N.; Klaman, Lori D.; Laskowitz, Daniel T.

doi:10.1097/aln.0b013e318253a02a

Cited by 24 publications

(27 citation statements)

References 37 publications

(36 reference statements)

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“…Microglial activation and macrophage recruitment are known mediators of cerebral edema formation and neurobehavioral outcome after ICH [63,64]. Iba-1 staining was performed at 7 days after ICH induction in the male rats.…”

Section: Resultsmentioning

confidence: 99%

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

Hsieh¹,

Lei²,

Sheng³

et al. 2015

Neuroendocrinology

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Background: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. Methods: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. Results: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-κB p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. Conclusions: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.

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Section: Resultsmentioning

confidence: 99%

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

Hsieh¹,

Lei²,

Sheng³

et al. 2015

Neuroendocrinology

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“…A priori and post hoc exclusion criteria were limited to surgical complications and failure of drug/vehicle delivery or thermoregulation. Based on known variance within this model, (Indraswari et al, 2012;James et al, 2010James et al, , 2012Laskowitz et al, 2007;Lynch et al, 2005;Wang et al, 2007Wang et al, , 2013 sample size of 15-19 mice per group was calculated to demonstrate a 30% treatment effect in MWM latencies over days 29-32 after injury for a 3-group repeated measures ANOVA. A p value b 0.05 was considered statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…Timepoints were chosen to capture early neuronal degeneration, subacute microglial activation/macrophage recruitment, and long-term neuronal survival, respectively, based on model experience (Indraswari et al, 2012;James et al, 2010James et al, , 2012Laskowitz et al, 2007;Lynch et al, 2005;Wang et al, 2007Wang et al, , 2013. Separate cohorts of mice were used for FJB (n = 8/group) and F4/80 staining (n = 6/group); NeuN staining occurred in the same cohort as MWM (n = 6/group).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…This timepoint was chosen to fall within the period of peak edema based on model experience (Indraswari et al, 2012;James et al, 2010James et al, , 2012Laskowitz et al, 2007;Lynch et al, 2005;Wang et al, 2007Wang et al, , 2013. Brains were excised and, after removing the cerebellum and brainstem, were weighed immediately ("wet" weight) by an examiner blinded to treatment assignment.…”

Section: Brain Water Contentmentioning

confidence: 99%

“…The concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured by an examiner blinded to treatment assignment at 4 h and 24 h after injury, using Quantikine ELISA kits (R&D Systems; Minneapolis, MN) according to the manufacturer's instructions. These timepoints were chosen to capture early microglial/macrophage activation and fall within the period of peak edema based on model experience (Indraswari et al, 2012;James et al, 2010James et al, , 2012Laskowitz et al, 2007;Lynch et al, 2005;Wang et al, 2007Wang et al, , 2013.…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

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Intravenous immunoglobulin G improves neurobehavioral and histological outcomes after traumatic brain injury in mice

Jeong

Lei

Wang

et al. 2014

Journal of Neuroimmunology

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First‐in‐human studies of MW01‐6‐189WH, a brain‐penetrant, anti‐neuroinflammatory, small molecule drug candidate: Phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic studies in healthy adult volunteers

Eldik

Roy

Guptill

2020

Alzheimer's & Dementia

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Background Acute brain injuries, such as intracerebral hemorrhage (ICH) or traumatic brain injury (TBI), are major medical problems that cause considerable mortality and morbidity in older individuals. In addition to the initial injury, secondary neuroinflammatory events can further damage the brain and lead to increased risk of neurologic complications, including Alzheimer’s disease (AD) and related dementias (ADRD). A specific aspect of neuroinflammation, injury‐induced proinflammatory cytokine overproduction from abnormally activated glia, has been linked to subsequent neurological damage and cognitive deficits in both acute and chronic CNS disorders. Despite advances in our understanding of these molecular neuroinflammatory mechanisms, approved therapeutics that target this pathological process are lacking. To address this need, we developed a CNS‐penetrant, small molecule drug candidate, MW01‐6‐189WH (=MW189), that selectively attenuates stressor‐induced proinflammatory cytokine overproduction. MW189 is efficacious at low doses in animal models of AD, TBI and ICH. Based on promising drug‐like properties, preclinical efficacy, and excellent safety profile, an intravenous formulation of MW189 was developed and tested in phase 1 human studies. Methods Phase 1 studies were done to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of MW189 in healthy adults. A pilot pharmacodynamic study administering low dose endotoxin to induce a systemic inflammatory response was done to evaluate effects of a single dose of MW189 on plasma cytokine levels. Results MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. No clinically concerning changes were seen in vital signs, ECGs, physical or neurological examinations, or safety laboratory results. PK analysis showed dose‐proportional increases in MW189 plasma concentrations after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. In the pilot pharmacodynamic study, MW189 treatment resulted in lower plasma levels of the proinflammatory cytokine TNFα and higher levels of the anti‐inflammatory cytokine IL‐10 compared to placebo treatment, suggesting engagement of pharmacological mechanism. Conclusion Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute CNS injury, AD/ADRD, or other disorders involving dysregulated neuroinflammation as a driver of disease progression.

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TT-301 Inhibits Microglial Activation and Improves Outcome after Central Nervous System Injury in Adult Mice

Cited by 24 publications

References 37 publications

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

Intravenous immunoglobulin G improves neurobehavioral and histological outcomes after traumatic brain injury in mice

First‐in‐human studies of MW01‐6‐189WH, a brain‐penetrant, anti‐neuroinflammatory, small molecule drug candidate: Phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic studies in healthy adult volunteers

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