S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway

Harikesh Dubey; Arunabha Ray; Anamika Dubey; Kavita Gulati

doi:10.1159/000538348

S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway

Neuropsychobiology. 2024 May 14:1-13. doi: 10.1159/000538348. Online ahead of print.

Authors

Harikesh Dubey^{1

2}, Arunabha Ray^{1

3}, Anamika Dubey¹, Kavita Gulati¹

Affiliations

¹ Departments of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India.
² The Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, USA.
³ Departments of Pharmacology, Hamdard Institute of Medical Sciences and Research (HIMSR), Hamdard University, New Delhi, India.

PMID: 38744261
DOI: 10.1159/000538348

Abstract

Introduction: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains.

Method: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aβ)-40, Aβ42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue.

Results: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aβ levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats.

Conclusion: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Keywords: Alzheimer’s disease; Amyloid beta; Intracerebroventricular infusion of streptozotocin; Nitric oxide; Nuclear factor erythroid 2-related factor-2 and brain-derived neurotrophic factor; S-nitrosoglutathione; Streptozotocin.