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Preclinical Study of the Neuroprotective Effects of Pharmacological Agent-Modulators of HSP70 After Intrauterine
Igor Belenichev1, Olena Aliyeva2, Nina Bukhtiyarova3
1Department of Pharmacology and Medical Formulation with Course of Normal Physiology, Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine.
Insights
Chronic intrauterine hypoxia (IUH) impairs offspring brain development. HSP70 modulators, particularly angiolin and cerebrocurin, show promise in protecting against long-term neurological damage by improving endothelial function and neurotrophic support.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Chronic intrauterine hypoxia (IUH) is linked to postnatal mortality and delayed central nervous system (CNS) impairments.
- These impairments include increased risks of cerebrovascular disorders, epilepsy, and neurodegenerative diseases.
- Targeted neuroprotective strategies are crucial for newborns affected by IUH.
Purpose of the Study:
- To evaluate the neuroprotective effects of 70 kDa heat shock protein (HSP70) modulators on molecular markers in offspring brains post-IUH.
- To assess the impact of angiolin, thiotriazolin, cerebrocurin, tamoxifen, glutaredoxin, and heat shock factor 1 (HSF-1) on endothelial dysfunction and neurotrophic factors.
Main Methods:
- Chronic IUH was induced in pregnant rats using sodium nitrite.
- Male offspring were treated with study drugs for 30 days, starting on postnatal day 1.
- Brain homogenates were analyzed for VEGF-A, eNOS, iNOS, nitrotyrosine, BDNF, NGF, and caspase-8 levels at 30 and 60 days of age.
Main Results:
- IUH induced persistent endothelial dysfunction, nitrosative stress, decreased neurotrophin levels (BDNF, NGF), and increased caspase-8.
- Angiolin, cerebrocurin, HSF-1, thiotriazolin, and glutaredoxin improved the eNOS/iNOS balance and reduced nitrosative stress.
- Cerebrocurin and angiolin showed the strongest recovery of neurotrophic factors and suppressed caspase-8 effectively, with positive correlation to BDNF, NGF, and HSP70.
Conclusions:
- HSP70 modulators offer multimodal neuroprotection through endothelioprotective and neurotrophic effects.
- Angiolin and Cerebrocurin demonstrate significant therapeutic potential for mitigating long-term neurological sequelae of IUH.
Background:
Chronic intrauterine hypoxia (IUH) is a cause not only of early postnatal mortality but also of delayed central nervous system (CNS) impairments in offspring, including increased risks of acute cerebrovascular disorders, epilepsy, and neurodegenerative diseases. The above necessitates the urgent development of targeted neuroprotective strategies for newborns following IUH. The aim of the present study was to evaluate the neuroprotective effects of the 70 kDa heat shock protein (HSP70) modulators (angiolin, thiotriazolin, cerebrocurin, tamoxifen, glutaredoxin, and heat shock factor 1 (HSF-1)), as well as reference drugs, based on their impact on molecular markers of endothelial dysfunction (vascular endothelial growth factor A (VEGF-A), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and caspase-8 in the brains of offspring after IUH at 1 and 2 months of age.
Methods:
Chronic hemic IUH was modeled in pregnant rats by daily administration of sodium nitrite (50 mg/kg, intraperitoneally) on days 16-21 of pregnancy. The male offspring were treated with the study drugs for 30 days starting on P1. Brain homogenates of offspring at P30 and P60 were analyzed using enzyme-linked immunosorbent assay (ELISA) for VEGF-A, eNOS, iNOS, nitrotyrosine, BDNF, NGF, and caspase-8.
Results:
IUH caused persistent endothelial dysfunction, characterized by decreased VEGF and eNOS levels, and nitrosative stress, associated with increased iNOS and nitrotyrosine levels. These changes were accompanied by decreased neurotrophin levels, including BDNF and NGF, and increased caspase-8 levels. Course administration of angiolin, cerebrocurin, HSF-1, thiotriazolin, and glutaredoxin improved the eNOS/iNOS balance, increased VEGF levels, and decreased nitrotyrosine levels, with the effect persisting until P60. Cerebrocurin and angiolin demonstrated the strongest recovery of neurotrophic factors (normalization or exceeding normal BDNF/NGF levels by P60) and effectively suppressed caspase-8 to near-normal levels. A positive correlation was established between BDNF, NGF, and HSP70 levels.
Conclusions:
Pharmacological modulators of HSP70 provide effective multimodal neuroprotection due to endothelioprotective and neurotrophic effects. Angiolin and Cerebrocurin demonstrate significant therapeutic potential, offering a promising strategy for mitigating the long-term neurological sequelae of IUH.
