Synergic Effect of Early Administration of Probiotics and Adipose-Derived Mesenchymal Stem Cells on Alleviating Inflammation-Induced Chronic Neuropathic Pain in Rodents

Int J Mol Sci. 2022 Oct 9;23(19):11974. doi: 10.3390/ijms231911974.

Abstract

This study investigated the hypothesis that probiotics enhanced the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on alleviating neuropathic pain (NP) due to chronic constriction injury (CCI) mainly through regulating the microbiota in rats. SD rats (n = 50) were categorized into group 1 (sham-control), group 2 (NP), group 3 (NP + probiotics (i.e., 1.5 billion C.F.U./day/rat, orally 3 h after NP procedure, followed by QOD 30 times)), group 4 (NP + ADMSCs (3.0 × 105 cells) 3 h after CCI procedure, followed by QOD six times (i.e., seven times in total, i.e., mimic a clinical setting of drug use) and group 5 (NP + probiotics + ADMSCs (3.0 × 105 cells)) and euthanized by day 60 after NP induction. By day 28 after NP induction, flow-cytometric analysis showed circulating levels of early (AN-V+/PI−) and late (AN-V+/PI+) apoptotic, and three inflammatory (CD11b-c+, Ly6G+ and MPO+) cells were lowest in group 1 and significantly progressively reduced in groups 2 to 5 (all p < 0.0001). By days 7, 14, 21, 28, and 60 after CCI, the thresholds of thermal paw withdrawal latency (PWL) and mechanical paw withdrawal threshold (PWT) were highest in group 1 and significantly progressively increased in groups 2 to 5 (all p < 0.0001). Numbers of pain-connived cells (Nav1.8+/peripherin+, p-ERK+/peripherin+, p-p38+/peripherin+ and p-p38+/NF200+) and protein expressions of inflammatory (p-NF-κB, IL-1ß, TNF-α and MMP-9), apoptotic (cleaved-caspase-3, cleaved-PARP), oxidative-stress (NOX-1, NOX-2), DNA-damaged (γ-H2AX) and MAPK-family (p-P38, p-JNK, p-ERK1/2) biomarkers as well as the protein levels of Nav.1.3, Nav.1.8, and Nav.1.9 in L4-L5 in dorsal root ganglia displayed an opposite pattern of mechanical PWT among the groups (all p < 0.0001). In conclusion, combined probiotic and ADMSC therapy was superior to merely one for alleviating CCI-induced NP mainly through suppressing inflammation and oxidative stress.

Keywords: adipose-tissue-derived mesenchymal stem cells; chronic constriction injury; neuropathic pain; probiotics.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Caspase 3 / metabolism
  • DNA / metabolism
  • Inflammation / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mesenchymal Stem Cells* / metabolism
  • NF-kappa B / metabolism
  • Neuralgia* / drug therapy
  • Neuralgia* / therapy
  • Peripherins / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Probiotics* / pharmacology
  • Probiotics* / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Rodentia / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Biomarkers
  • NF-kappa B
  • Peripherins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Necrosis Factor-alpha
  • DNA
  • Caspase 3
  • Matrix Metalloproteinase 9