PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury

Abstract

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury. Here, we assessed several PHLPP inhibitors not previously explored for neuroprotection (NSC13378, NSC25247, and NSC74429) that had favorable predicted chemistries for targeting the central nervous system (CNS). Neuronal culture studies in staurosporine (apoptosis), glutamate (excitotoxicity), and hydrogen peroxide (necrosis/oxidative stress) revealed that NSC74429 at micromolar concentrations was the most neuroprotective. Subsequent testing in a rat model of asphyxial cardiac arrest, and in a mouse model of severe TBI, showed that serial dosing of 1 mg/kg of NSC74429 over 3 days improved hippocampal survival in both models. Taken together, NSC74429 is neuroprotective across multiple insult mechanisms. Future pharmacokinetic and pharmacodynamic (PK/PD) studies are warranted to optimize dosing, and mechanistic studies are needed to determine the percentage of neuroprotection mediated by PHLPP1/2 inhibition, or potentially from the modulation of PHLPP-independent targets.

Cardiac Arrest in Traumatic Brain Injury

“…Jackson et al 4) evaluated compounds NSC13378, NSC25247, and NSC74429 in animal models, highlighting promising chemical characteristics for potential CNS targeting. Before this study, no research on neuroprotection using PHLPP inhibitors had been conducted.…”

“…The pathophysiology of cardiac arrest in TBI involves a myriad of interacting factors. Elevated intracranial pressure, alterations in cerebral autoregulation, heightened sympathetic activity, and the incidence of secondary brain injuries are among the identified risk factors [2][3][4][5] . The objective of this study was to explore the intricate relationship between cardiac arrest and TBI, elucidating the underlying mechanisms, risk factors, and potential therapeutic options that may con-tribute to overall outcomes (Fig.…”

“…The objective of this study was to explore the intricate relationship between cardiac arrest and TBI, elucidating the underlying mechanisms, risk factors, and potential therapeutic options that may con-tribute to overall outcomes (Fig. 1) [2][3][4][5] .…”

Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets

“…Other studies have recently highlighted the significance of multifaceted approaches to enhance neuronal survival. In particular, Pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) inhibitors, such as NSC74429, have shown promise in protecting against the damaging effects of oxidative stress triggered by hydrogen peroxide and excitotoxicity induced by glutamate [94]. Furthermore, hydrogen sulfide (H 2 S), a newly recognized gaseous neurotransmitter, has demonstrated neuroprotective effects by reducing oxidative stress associated with glutamate, potentially through the p53/glutaminase 2 pathway [95].…”