Analysis of PTEN Antagonistic Peptides (PAPs) in Neuronal Growth and Traumatic Brain Injury (TBI)

PTEN (phosphatase and tensin homologue) is an established cellular growth brake whose inhibition stimulates regeneration of injured neurons in rodent models. Herein, we employed peptide-based PTEN inhibition targeting PTEN's phosphatase activity. Therefore, a fusion peptide (PAP2-TAT) of PAP2 (PTEN antagonistic peptide 2) with TAT (transactivator of transcription) was used to enable cellular entry. PAP2-TAT was not cytotoxic and entered the cytoplasm of primary mouse neurons, where it enhanced neurite growth, growth cone size, and synaptophysin abundance. PAP2-TAT modestly elevated P-AKT and more strongly elevated P-ERK levels. Furthermore, STATs (signal transducer and activator of transcription) were phosphorylated after PAP2-TAT administration. So far, PAPs have not been employed in traumatic brain injury (TBI). In a mouse TBI model, a single PAP2-TAT injection improved single parameters of gait impairments but had no impact on neuroinflammation and TBI-associated weight loss. In summary, peptide-based PTEN inhibition aids neuronal cell growth and regeneration after brain injury.