Dipeptidyl Peptidase (DPP)-4 Inhibitors and Pituitary Adenylate Cyclase-Activating Polypeptide, a DPP-4 Substrate, Extend Neurite Outgrowth of Mouse Dorsal Root Ganglia Neurons: A Promising Approach in Diabetic Polyneuropathy Treatment.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Ganglia, Spinal*/metabolism ; Ganglia, Spinal*/drug effects ; Dipeptidyl-Peptidase IV Inhibitors*/pharmacology ; Pituitary Adenylate Cyclase-Activating Polypeptide*/pharmacology ; Neuronal Outgrowth*/drug effects ; Diabetic Neuropathies*/drug therapy ; Diabetic Neuropathies*/metabolism; Animals ; Mice ; Neuropeptide Y/metabolism ; Neuropeptide Y/pharmacology ; Chemokine CXCL12/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Linagliptin/pharmacology ; Dipeptidyl Peptidase 4/metabolism ; Sitagliptin Phosphate/pharmacology ; Cells, Cultured ; Neurites/drug effects ; Neurites/metabolism ; Oligopeptides

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.

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Keywords: diabetic polyneuropathy; dipeptidylpeptidase-4; neurite outgrowth of dorsal root ganglia neurons; pituitary adenylate cyclase-activating polypeptide

0 (Dipeptidyl-Peptidase IV Inhibitors)
0 (Pituitary Adenylate Cyclase-Activating Polypeptide)
0 (Neuropeptide Y)
0 (Chemokine CXCL12)
90614-48-5 (diprotin A)
3X29ZEJ4R2 (Linagliptin)
EC 3.4.14.5 (Dipeptidyl Peptidase 4)
TS63EW8X6F (Sitagliptin Phosphate)
0 (Oligopeptides)

Date Created: 20240829 Date Completed: 20240829 Latest Revision: 20240903

20240903

PMC11354620

10.3390/ijms25168881

39201570