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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein–dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

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Introduction: The alpha7 nicotinic acetylcholine receptor (α7nAChR) is the principal mediator of the cholinergic anti-inflammatory pathway (CAP). CAP is mediated through several signaling pathways, including the JAK2/ STAT3 pathway. Studies have shown decrease in brain α7nAChR and increase in phosphorylation (p) of JAK2 and STAT3 expression after stroke. Increase JAK2/STAT3 signaling induces expression of high mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE), which promotes release of cytokines. Pharmacological activation of α7nAChR reduced microglial activation and inflammatory cytokines and improved functional outcomes after experimental stroke. However, little is known about how the activation of α7nAChR modulates JAK2/STAT3 signaling after stroke. Hypothesis: We hypothesized α7nAChR activation by PNU120596 (PNU), an allosteric modulator will decrease JAK2/STAT3 signaling and improve neurological deficits (ND) after stroke. Methods: Young (8-12 weeks, n=5-6) male mice underwent 60-minute middle cerebral artery occlusion (MCAo) or sham surgery and euthanized at 24 hours. In second cohort (n=5-6), PNU or vehicle was administered for 3 consecutive days. One hour after the last injection, MCAo or sham surgery was done. Twenty-four hours after MCAo, body weight, ND scores were recorded and brains harvested for western blotting. Brain α7nAChR, pSTAT3, HMGB1 and RAGE expression was determined. Results: At 24 hours after MCAo, the brain expression of α7nAChR decreased (p=0.006) while pSTAT3 expression increased (p=0.001) as compared to sham. PNU treatment prevented a decrease in α7nAChR expression in the brain (p=0.017) and decreased pSTAT3 expression (p=0.005) compared to the vehicle group after MCAo. No difference in the HMGB1 expression was seen between groups. An increase in RAGE expression was observed in vehicle MCAo (p=0.006) compared to sham. A decline (p=0.08) in RAGE expression in PNU MCAo compared to vehicle MCAo was observed. NDS and percent body weight loss were lower in the PNU MCAo compared to vehicle MCAo. Conclusions: Activation of α7nAChR downregulated inflammatory JAK2/STAT3-HMGB1/RAGE signaling and may be a druggable target to improve recovery after stroke.

Introduction: With aging, microglia acquire a dysfunctional phenotype characterized by dystrophic morphology, impaired phagocytosis, reduced motility, and an exaggerated response to injury. Microglia become pathologically activated with aging and play a detrimental role in age-associated cognitive decline and neurodegenerative diseases. Older mice exhibit a differential response to stroke and have worse outcomes despite smaller infarcts compared to young mice. Microglia from aged mice produce higher levels of reactive oxidative species and have an exaggerated inflammatory response after ischemic stroke. Hypothesis: We hypothesized that ablation of microglia would reduce the exaggerated neuroinflammatory responses in aged mice and loss of microglia would improve early recovery after ischemic stroke. Aged (18-19 months) male mice were fed a control chow diet (CD) or PLX5622 chow diet (PLXD) for 21 days. On day 22, 60-minute middle cerebral artery occlusion (MCAo) or sham surgery was performed. Twenty-four hours after MCAo, neurological deficit scores (NDS) and immunohistochemistry assessments, as well as flow cytometry, were performed. Results: There was a significant reduction in Iba1 + cells in striatum and cortex of the aged mice with PLX treatment: day 7 (p<0.05), day 14 (p<0.001), and day 21 (p<0.001) vs day 0. Twenty-four hours after MCAo, the NDS were not different between CD (3.0±0.18) and PLXD (2.92±0.21). However, an increase in infarct size was seen in the aged PLXD group compared to the aged CD group (p<0.05). After MCAo, there was an increase in infiltrating monocytes and neutrophils in both diet groups compared to their respective shams (p<0.05). However, an increase in infiltrating monocytes was observed in the PLXD MCAo vs. CD MCAo (p<0.0001) reflecting a differential monocyte response in animals without microglia. Additionally, a decrease in NeuN immunoreactivity was seen in the PLXD MCAo group compared to PLXD sham (p<0.01). GFAP + cells increased in PLXD sham group as compared to CD sham (p<0.05). Conclusions: Our results suggest that microglia are essential immune cells that surprisingly limit immune cell infiltration, decrease neuronal degeneration, and reduce neuroinflammation after ischemic stroke in aged mice.