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. 2024 Jul 30;16(7):e65726.
doi: 10.7759/cureus.65726. eCollection 2024 Jul.

Effect of New Antidiabetics on Steatosis in Nerve Tissues and Nerve Conduction Velocity: Possible Role of Nerve Growth Factor (NGF)/Synaptophysin and Nrf2/HO-1 Pathways

Nehal H M Abdel-Halim  1 , Elsayed A Eid  2 , Yomna M Yehya  1 , Medhat Taha  3   4 , Ahmed A H Mosa  5 , Omar Ammar  6 , Ahmed N A Nasr  4 , Emadeldeen Hussin  4 , Abdelaziz M Hussein  1
Affiliations

Effect of New Antidiabetics on Steatosis in Nerve Tissues and Nerve Conduction Velocity: Possible Role of Nerve Growth Factor (NGF)/Synaptophysin and Nrf2/HO-1 Pathways

Nehal H M Abdel-Halim et al. Cureus. .

Abstract

Objectives: The current study aims to investigate the impact of the GLP1 analog (semaglutide) and SGLT2 inhibitor (dapagliflozin) on nerve functions, morphology, and the underlying mechanisms involving nerve growth factor (NGF)/synaptophysin and Nrf2/HO-1 pathways in obese rats.

Methods: Forty male Sprague Dawley rats, aged six to eight weeks, were classified into five groups; normal group (high-fat diet {HFD} for 12 weeks, metformin group (HFD for 12 weeks + metformin in last four weeks), dapagliflozin group (HFD for 12 weeks +dapagliflozin in last four weeks, semaglutide group (HFD for 12 weeks + semaglutide in last four weeks). At the end of the experiment, the sciatic nerve was collected for nerve conduction study, oxidative stress marker (malondialdehyde, i.e., MDA), real-time polymerase chain reaction (PCR) study (for HO-1 and Nrf2), oil red O staining, electron microscopic examination and immunohistochemistry for NGF and synaptophysin.

Results: The HFD group showed a significant rise in blood glucose, serum lipids, homeostatic model assessment (HOMA) index, lipid deposition in nerve tissues, and lipid peroxidation (MDA) in nerve tissues with significant attenuation in nerve conduction velocity (NCV), the expression of Nrf2 and HO-1 genes and significant attenuation in area stained with NGF and synaptophysin. On the other hand, pretreatment with either dapagliflozin or semaglutide led to considerable enhancement in the deteriorated serum and nerve tissue parameters and reversed the pathological changes.

Conclusion: New antidiabetic drugs like SGLT2 inhibitors (more powerful) and GLP1 analog might have neuroprotective beneficial effects besides controlling the glycemic state in obese rats. This effect may result from reduced oxidative stress and increased Nrf2 levels, HO-1, synaptophysin, and NGF in the nerve tissues of obese rats.

Keywords: dapa; nerve conduction velocity; ngf/synaptophysin; nrf2/ho-1; obese; semaglutide.

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Conflict of interest statement

Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: Ethics Committee, Medical Experimental Research Center (MERC), Mansoura University Issued protocol number R.21.12.1551. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1
Figure 1. Nerve conduction study on isolated sciatic nerve.
(A) NCV (m/sec) in isolated sciatic nerve in all experimental groups; (B) NCV traces normal group; (C) NCV traces in the HFD group; (D) NCV traces in the metformin group; (E) NCV traces in dapagliflozin (Dapa) group; and (F) NCV traces in semaglutide group. NCV, nerve conduction velocity; HFD, high-fat diet.
Figure 2
Figure 2. Oxidative stress markers and expression of antioxidant genes in the sciatic nerve.
(A) MDA concentration (nmol/g nerve tissues) in nerve tissues in all studied groups; (B) relative expression of Nrf2 at mRNA level; and (C) relative expression of HO-1 at mRNA level in the sciatic nerve. Variables were expressed as mean±SD. *** p<0.001 significant vs normal group; ### p<0.001 significant vs HFD group; $$$ p<0.001 significant vs metformin group; ††† p<0.001 significant vs dapagliflozin (Dapa) group. MDA, malondialdehyde; HFD, high-fat diet.
Figure 3
Figure 3. Oil red O staining for fat accumulation in the sciatic nerve.
(A) Score of oil red O stain in the sciatic nerve in different studied groups; (B-F) representative samples of oil red O stain from normal, HFD, metformin, dapagliflozin (Dapa), and semaglutide groups respectively (lipid content stained by oil red O stain, blue arrows). Variables were expressed as mean±SD. *** p<0.001 significant vs normal group; ### p<0.001 significant vs HFD group; $$$ p<0.001 significant vs metformin group; and ††† p<0.001 significant vs dapagliflozin (Dapa) group. HFD, high-fat diet; ROI, region of interest.
Figure 4
Figure 4. H&E staining for the sciatic nerve in all experimental groups.
(A) Normal group (400x) shows normal and regular arrangement of nerve fibers; (B) HFD group (400x) shows irregular arrangement of nerve fibers with wide spacing and interstitial edema and perineural vacuolization (fatty depositions, blue arrows) (400x); (C) semaglutide group shows irregular arrangement of nerve fibers and interstitial edema (blue arrows) (400x); (D) metformin group shows nearly normal and regular arrangement of nerve fibers (400x); and (E) dapagliflozin group shows regular arrangement of nerve fibers (400x). H&E, hematoxylin and eosin; HFD, high-fat diet.
Figure 5
Figure 5. EM examination of the sciatic nerve in all experimental groups.
(A) The number of myelinated nerve fibers in the sciatic nerve; (B) percentage of abnormal myelinated nerve fibers; (C) g-ratio for small-sized nerve fibers; (D) medium-sized nerve fibers; and (E) large-sized nerve fibers. Photomicrographs using a TEM for (F) normal group; (G) HFD group; (H) semaglutide group; (I) metformin group; and (J) dapagliflozin (Dapa) group, all in magnification 12000x. Variables were expressed as mean±SD. *** p<0.001 significant vs normal group; ### p<0.001 significant vs HFD; $$$ p<0.001 significant vs metformin; and ††† p<0.001 significant vs dapagliflozin (Dapa) group. EM, electron microscope; TEM, transmission electron microscope; HFD, high-fat diet.
Figure 6
Figure 6. Expression of NGF in immunohistochemical results.
(A) Mean of NGF area (ROI) per HPF; immunostaining for NGF shows brown cytoplasmic staining in (B) control group, (C) HFD group, (D) metformin group, (E) dapagliflozin (Dapa) group, and (F) semaglutide group. (B-F) All in magnification 400x. Variables were expressed as mean±SD. *** p<0.001 significant vs normal group; ### p<0.001 significant vs HFD, $$$ p<0.001 significant vs metformin, and ††† p<0.001 significant vs dapagliflozin (Dapa) group. NGF, nerve growth factor; ROI, region of interest; HPF, high-power field; HFD, high-fat diet.
Figure 7
Figure 7. Expression of synaptophysin in immunohistochemical results.
(A) Mean of synaptophysin area (ROI) per HPF; immunostaining for synaptophysin shows brown cytoplasmic staining in (B) control group, (C) HFD group, (D) metformin group, (E) dapagliflozin (Dapa) group, and (F) semaglutide group. (B-F) All in magnification 400x. Variables were expressed as mean±SD. *** p<0.001 significant vs normal group, ### p<0.001 significant vs HFD, $$$ p<0.001 significant vs metformin, and ††† p<0.001 significant vs dapagliflozin (Dapa) group. ROI, region of interest; HPF, high-power field; HFD, high-fat diet.
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