Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice

Abstract

Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvβ3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.

Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity in Rats

“…Iba-1 is a selective microglial marker protein that reflects active microglial cells [ 69 ]. Our results indicated that 3-NP dramatically elevated the expression of Iba-1 + microglia and alters the expression/release of the pro-inflammatory factors, TNF-α, IL-1β, IL-6, and NF-κB, which is corroborated by several studies [ 70 – 73 ]. After treatment with PIO or TEL, we detected the repression of these inflammatory factors as a result of inhibition of both striatal microglial cells and NF-κB expression.…”

Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis

“…Several agents that aim to suppress the infiltration of leukocytes and the activation of macrophages/microglia in the CNS have been developed as potential therapies for MS (Cai et al., 2018 ). The effects of the compounds of C16 and Ang-1 on CNS inflammatory-related diseases have been confirmed using a variety of animal models (Han et al., 2010 ; Aarts et al., 2017 ; Chen et al., 2019 ; Nakazato et al., 2020 ; Fu et al., 2021 ). Both at the peak (2 weeks pi) and later stage (4 weeks pi) of disease course, the C + A, nano-carrier C + A, or fMLP-nano-carrier C + A compounds reduced the number of CD14 + monocytes, CD68+ macrophages, CD45+ leukocytes, and CD4+ T lymphocytes, with the largest differences seen in the fMLP-nano-carrier C + A treatment group.…”