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

Xiao-Xiao Fu,Hong Jiang,Hua-Ying Cai,Shu Han

doi:10.18632/aging.203354

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.

Highlights

The neurological movement disorder, dystonia, is associated with abnormalities in various regions of the brain including the basal ganglia and cerebellum
In the Novel object recognition (NOR) test, the 3-Nitropropionic acid (3-NP)-treated mice spent around the same time scrutinizing novel and familiar objects, indicating a failure of spatial cognition discrimination (Figure 1F)
Given that the combined treatment of Ang-1 and C16 could synergistically inhibit inflammation [21], we explored the efficacy of C16+Ang-1 as a treatment option for dystonia by assessing the recovery of neuronal morphology and motor functions using an array of histological, immunohistochemical, biochemical, and electrophysiological experiments

Summary

Introduction

The neurological movement disorder, dystonia, is associated with abnormalities in various regions of the brain including the basal ganglia and cerebellum. Dystonia is characterized by involuntary repetitive contractions of antagonistic muscle groups that disrupt motor signals between the brain and neck, resulting in twisting movements and abnormal postures [1,2,3]. The different types of dystonia vary in etiology and phenotype, and symptoms can range from mild to severe [4, 5]. This disorder can occur as early as in childhood and its pathophysiology includes neuronal damage mainly in the striatum and nigra substance, as well as lesions in other regions of the brain [6]. As treatment options for dystonia are mainly symptomatic [8, 9], lack efficacy, and give rise to systemic toxicity [9], there is an imperative need for the development of new and effective alternative treatments as well as a cure

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