Novel insights into the nervous system affected by prolonged hyperglycemia

Abstract

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. Key messages Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.

Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice

“…We observed elevated levels of astrocytes and microglia with a simultaneous disappearance of motor neurons in ALS spinal cord [1,3,8]. We explain that in ALS astrocytes may lose their physiological functions and release proinflammatory cytokines and chemokines and thus trigger motor neuron degeneration in the spinal cord [1,3,7,9,10]. Studies showed that hyperactive astrocytes were found in the ventral horn of ALS patients and mice [1,9,10].…”

“…We explain that in ALS astrocytes may lose their physiological functions and release proinflammatory cytokines and chemokines and thus trigger motor neuron degeneration in the spinal cord [1,3,7,9,10]. Studies showed that hyperactive astrocytes were found in the ventral horn of ALS patients and mice [1,9,10]. Moreover, the results indicated that Glial Fibrillary Acidic Protein (GFAP) positive astrocytes revealed proinflammatory factors, such as: cytokines as well as RAGE proinflammatory ligands [1,9,10].…”

“…The obtained cDNA was used for quantitative PCR analysis (Table 1). The expressions of mRNA transcripts of genes encoding HMGB1, S100B [6], ras homolog family member J (RHOJ) [10] were investigated in duplicate by SYBR1 Green PCR Master Mix (Qiagen, Hilden, Germany) and a LightCycler1 480 Instrument II (Roche Molecular Systems, Inc., Switzerland). The initial denaturation at 95˚C for 10 min was followed by 40 cycles of denaturation at 95˚C for 5 s, primer annealing at 62˚C for 10 s, and elongation at 72˚C for 10 second.…”

“…The relative expression of mRNAs was calculated by ΔΔCt method and normalized using the geometric mean of expression levels of housekeeping genes, i.e. importin 8 (IPO8) [6] and 18S ribosomal RNA (18S rRNA) [10,11].…”

“…Studies showed that hyperactive astrocytes were found in the ventral horn of ALS patients and mice [1,9,10]. Moreover, the results indicated that Glial Fibrillary Acidic Protein (GFAP) positive astrocytes revealed proinflammatory factors, such as: cytokines as well as RAGE proinflammatory ligands [1,9,10]. Elevated expression of proinflammatory proteins may trigger RAGE signaling pathway and thus motor neurons degeneration during progression of ALS [1][2][3][4][5][6][7].…”