Year: 2023
Type: article
Abstract: AIM: This study aims to compare the effects of VIP and PACAP-38 on the upper and lower motor neurons in SOD1G93A mice, a reliable model for human ALS disease.METHODS: Transgenic SOD1G93A and wild-type mice, representing different stages of ALS, were divided into experimental groups: Control (n=10), ALS+SF (n=10), ALS+VIP (n=10), and ALS+PACAP (n=10).In each stage, chronic intraperitoneal (i.p.) injections were administered as follows: ALS+SF group received saline (SF), ALS+VIP group received 5nmol/kg VIP i.p., and ALS+PACAP group received 25ng/kg PACAP i.p.At the pre-symptomatic stage on day P30, qualitative analysis was performed using transmission electron microscopy (TEM) to visualize structural changes in motor neurons at the L3-L4 spinal cord segment.These changes included mitochondrial differences, cytoplasmic vacuolization, and alterations in axo-dendritic and axo-somatic synapses.At the symptomatic stage on day P105, samples were collected from the primary motor cortex using microdialysis, and ultra-high-performance liquid chromatography (UHPLC) analysis was conducted to measure glutamate, GABA, and GSH levels.Motor neurons with different soma sizes were quantified in Nissl-stained spinal cord sections at the L3-L4 level.Dendritic spine densities of motor neurons were assessed in Golgi-Cox stained spinal cord sections at the same level.Microglial morphology was analyzed using stereological counting in Iba1immunoreactive spinal cord sections.From the pre-symptomatic stage at P30 to post-symptomatic P120, motor performance was measured using the rotarod test, and weight and survival evaluations were conducted (survival was assessed using Kaplan-Meier analysis).Subsequently, molecular mechanisms related to neurodegeneration in spinal cord tissue were investigated.Inflammatory markers (TNF-α, IL1-β, IL-6, IL1-0, NFκB, CD11b), growth factors (BDNF, IGF-, FGF2), a reactive astroglia marker (GFAP), and astroglial glutamate transporter (GLT-1) gene expression levels were analyzed using quantitative PCR (qPCR) method.The obtained findings were statistically evaluated using one-way ANOVA and multiple comparisons were performed using the Tukey HSD test.RESULTS: In the pre-symptomatic stage, it was observed that the overall morphology of motor neurons, nuclear morphology, mitochondrial morphology, and myelin structures in the ALS+SF groups in the lumbar spinal cord ventral horn showed morphology close to the control group, while in the ALS+VIP and ALS+PACAP groups, in the symptomatic stage, the total number of motor neurons (p<0.001) and dendritic spine density (p<0.01) in the ALS+PACAP group and only dendritic spine density (p<0.05) in the ALS+VIP group significantly increased compared to the ALS+SF group.It was also found that the number of reactive microglia significantly decreased in the ALS+VIP and ALS+PACAP groups compared to the ALS+SF group (p<0.0001).In the postsymptomatic stage, it was observed that motor performance significantly improved in the ALS+PACAP group, and the survival time significantly extended in the ALS+VIP (p<0.01) and ALS+PACAP (p<0.001) groups compared to the ALS+SF group.CONCLUSION: Both peptides have increased survival by preserving the ultrastructural changes of lower motor neurons, maintaining dendritic spine density, reducing neuroinflammation, and upregulating the expression of growth factors.As a result, while PAC-38 appears to be more effective in SOD1G93A ALS model mice, both VIP and PACAP-38 have shown therapeutic efficacy.
Source: Acta Physiologica
DOI: 10.1111/apha.14073
Authors: ÇAYLI, SEVİL, AKCAN, GÜLBEN, ATEŞOĞLU, RÜSTEM, BAYIROĞLU, FAHRİ, KAYA, MEHMET SALİH
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4389323270