Reduction in Nesfatin-1 Levels in the Cerebrospinal Fluid and Increased Nigrostriatal Degeneration Following Ventricular Administration of Anti-nesfatin-1 Antibody in Mice.

Huanhuan Chen,Wei Zheng,Xiaoli Shen,Xuelian Li,Hui Ma

doi:10.3389/fnins.2021.621173

Huanhuan Chen, Wei Zheng + Show 3 more

Open Access

https://doi.org/10.3389/fnins.2021.621173

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Abstract

Nesfatin-1 is one of several brain-gut peptides that have a close relationship with the central dopaminergic system. Our previous studies have shown that nesfatin-1 is capable of protecting nigral dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. A recent study also revealed a reduced blood level of nesfatin-1 in patients with Parkinson’s disease (PD). The current study was designed to investigate whether reduced nesfatin-1 in cerebrospinal fluid (CSF) induces nigrostriatal system degeneration. An intra-cerebroventricular (ICV) injection technique was used to administer anti-nesfatin-1 antibody directly into the lateral ventricle of the brain. Enzyme-linked immunosorbent assay (ELISA) results showed that ICV injection of anti-nesfatin-1 antibody into the lateral ventricle of the brain once daily for 2 weeks caused a significant reduction in nesfatin-1 levels in the CSF (93.1%). Treatment with anti-nesfatin-1 antibody resulted in a substantial loss (23%) of TH-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc), as shown by immunofluorescence staining, a depletion in dopamine and its metabolites in the striatum detected by high-performance liquid chromatography (HPLC), and obvious nuclear shrinkage and mitochondrial lesions in dopaminergic neurons in the SNpc detected by transmission electron microscopy (TEM). Furthermore, the results from our Western blot and ELISA experiments demonstrated that anti-nesfatin-1 antibody injection induced an upregulation of caspase-3 activation, increased the expression of p-ERK, and elevated brain-derived neurotrophic factor (BDNF) levels in the SNpc. Taken together, these observations suggest that reduced nesfatin-1 in the brain may induce nigrostriatal dopaminergic system degeneration; this effect may be mediated via mitochondrial dysfunction-related apoptosis. Our data support a role of nesfatin-1 in maintaining the normal physiological function of the nigrostriatal dopaminergic system.

Highlights

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the world (Dawson and Dawson, 2003; de Lau and Breteler, 2006; Elbaz et al, 2016)
The results presented in this study establish that (1) melanocortin 4 receptor (MC4R), a putative nesfatin-1 receptor, is expressed in dopaminergic neurons in the mouse substantia nigra pars compacta (SNpc); (2) daily ICV injection of nesfatin1 antibody greatly reduces nesfatin-1 levels in the cerebrospinal fluid (CSF); (3)
A reduced nesfatin-1 level in the CSF is associated with nigrostriatal dopaminergic system degeneration, as evidenced by the reduction in tyrosine hydroxylase (TH)(+) neurons, altered DA neurotransmitter levels, and impaired mitochondria and nuclei in the SNpc; and (4) the mechanism underlying DA neuron damage could involve dysfunctional apoptosis

Summary

Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the world (Dawson and Dawson, 2003; de Lau and Breteler, 2006; Elbaz et al, 2016). Several brain-gut peptides, such as neurotensin, ghrelin, and glucagon-like peptide-1, were identified to play a significant role in regulating the function of the brain dopaminergic system (St-Gelais et al, 2006; Calsolaro and Edison, 2015; Yu et al, 2016). Nesfatin-1, an 82-amino acid polypeptide that is a product of the NEFA/NUCB2 gene identified in 2006, has been shown to have anorexigenic properties (Oh et al, 2006; Stengel et al, 2010; Pałasz et al, 2012). Nesfatin-1 is relatively stable in the blood within 20 min after injection (Pan et al, 2007). This peptide can freely cross the blood-brain barrier in an unsaturated manner (Pan et al, 2007), allowing the delivery of nesfatin-1 into the brain by peripheral injection for the treatment of brain diseases (Dong et al, 2019)

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