Electroacupuncture modulates proNGF/mNGF ratio and stimulates neurogenesis in the dentate gyrus subgranular zone of diabetic rats.

Rationale: Diabetic Encephalopathy (DE) affects neurogenesis of the hippocampus (HP) dentate gyrus subgranular zone (SGZ)1,2 probably dysregulating the neurotrophic proNGF/mature-NGF (mNGF) system3, whose activity is regulated by the cholinergic neurotransmission from medial septum (MS)4. Electroacupuncture (EA) is effective in modulating proNGF/NGF balance and activity in the brain cholinergic system of DE rats3. Objectives: To study the effects of EA on the SGZ neurogenesis and on NGF receptors (TrkA and p75NTR) presence and activity in the MS in a rat model of DE. Materials and Methods: DE was induced in young adult rats by intraperitoneal streptozotocin (STZ). One week after STZ, EA treatment (burst frequency of 2 Hz, intensity 1.0-1.5 mA) was started and repeated twice a week for 3 weeks. At the end of the treatments, brain tissues representative of the cholinergic circuitry (HP and MS) were collected. Brain sections containing SGZ and MS regions were also collected. We analyzed: the mNGF/proNGF in HP by ELISA5; the number of doublecortin (DCX)-positive cells in SGZ by confocal microscopy; the distribution of p75NTR and TrkA in MS, together with markers of cholinergic phenotype and neuronal activity, by confocal microscopy; the activation of p75NTR pro-apoptotic signaling in MS by Western blot for the JNK/pospho-JNK system. Results: proNGF/mNGF ratio in HP was increased by STZ and normalized by EA. STZ also decreased and EA normalized the SGZ neurogenesis measured as number of DCX-positive cells. The number of cells immune-stained for p75NTR and TrkA in MS were increased and decreased respectively after STZ, while EA restored control levels. In MS, the EA reduced JNK phosphorylation, index of p75NTR-mediated pro-apoptotic activation, which increased after STZ. Conclusions: EA, probably normalizing the acetylcholine-mediated neurotransmission, stimulates the SGZ neurogenesis modulating the balance of proNGF/NGF, the cellular content of its receptors system and inhibiting p75NTR pro-apoptotic signal cascade.