Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis
Introduction
Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known ARMET, is a secreted protein [1], [2]. The gene encoding MANF is mapped to human chromosomal band 3p21 [3]. Belonging to the family of evolutionarily conserved dopamine neurotrophic factors, MANF has been found to have trophic effects on dopaminergic neurons and non-dopaminergic cells [4], [5]. Drosophila MANF is essential for maintenance of dopamine positive neurites and dopamine levels in the fly [6]. MANF is involved in the regulation of dopaminergic neuron development in zebrafish [7] and modulation of GABAergic transmission to the DA neurons of the substantia nigra [8].
MANF mRNA and protein were widely expressed in the brain [9]. The expression and secretion of MANF were enhanced after endoplasmic reticulum (ER) stress in cell lines [2], [10], [11], [12] and mouse models [13]. MANF was increased after epileptic insults and ischemia [2], [9], [14], [15]. Recent study showed that MANF was up-regulated in the activated glial cells under focal cerebral ischemia and in vitro ER stress or nutrient deprivation [16]. MANF was selectively secreted upon sarco ER calcium deletion [12]. Pretreatment with the recombinant human MANF significantly reduced the volume of infarction as well as improved the behavior in stroke rats [2], [17], [18]. However, the mechanisms are still unknown. In this study, we found that administration of recombinant human MANF protein after ischemic injury reduced the cerebral ischemia-induced neuron loss and promoted behavioral recovery in rats. Further, we found that MANF inhibited the cleavage of caspase-3, but not affected the expressions of ER stress-related proteins in the stroke rats. These results suggest that MANF rescues the neuron loss via inhibiting ischemia-induced apoptosis, which may shed light on the potential therapy of ischemic brain diseases.
Section snippets
Animals
Male Sprague Dawley rats (6 to 8 weeks old, weighing 150–200 g, license number is SCXK 2011–002) were obtained from the Anhui Experimental Animal Center (Hefei, China) and housed in SPF conditions for 1 week prior to experimentation. The animals had access to food and water ad libitum. All the experimental procedures for animal surgery were approved by the Ethics Committee of Anhui Medical University for Animal Experimentation and performed in accordance with the Guideline of the Declaration of
MANF promotes behavioral recovery and reduces the size of infarction induced by MCAO
To verify the protective effects of MANF on neurons during ischemia/reperfusion, MANF, diluted in PBS, was administrated to rat ipsilateral ventricle. PBS was injected as the vehicle control. Bederson's score, generally showing a negative relationship to the neurological deficit, was used to evaluate behavioral recovery before and after treatment. We found that Bederson's score was lower in the rats treated with MANF (1, 5, 10, and 20 μg) than that in the control rats from day 2 to day 14 after
Discussion
In this study, we found a protective effect of MANF on transient cerebral ischemia, in which MANF significantly reduced the size of cerebral infarction as well as improved the behavior in the stroke rats. There is an inverted U-shaped relationship between the doses and the effects of MANF. The maximal protective dose of MANF was 5 μg each rat. The underlying mechanisms are still unknown. It was probably associated with the saturability of MANF receptor or cofactor. This notion needs to be
Conflict of interest
The authors declare no conflict of interests.
Acknowledgment
This work was supported by grants (81372576, 81301060, 81173074 and 91129729) from the National Natural Science Foundation of China.
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2022, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :Our previous study has shown that MANF is expressed in immune cells and has an paracrine immune modulatory function, promoting functional recovery in a rat model of stroke.10 Similarly, endogenous MANF expression has been shown to be neuroprotective, as well as administration of MANF into the extracellular space.11-13 Therefore, MANF is possible to involve in the development of AIS and serve as a novel therapeutic agent for stroke.
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These authors contributed equally to this work.