The effect of antibodies to glutamate on the content of BDNF and GDNF in the brain structures of C57BL/6 mice upon intranasal administration of the neurotoxic fragment of β-amyloid protein Aβ₂₅₋₃₅

Abstract

Introduction. Neurotrophic factors are secreted proteins that play a key role in aging, neurodegeneration, and neuroinflammation in the brain. Brain-derived neurotrophic factors (BDNF) and glial-derived neurotrophic factors (GDNF) have been the most studied to date. BDNF and GDNF share common properties and play a key role in fundamental physiological processes in the central nervous system: proliferation, differentiation, maturation, and survival of neurons at all stages of pre- and postnatal neurogenesis, as well as synaptic plasticity. Cognitive impairment in neurodegenerative and neuroinflammatory processes in the brain, as well as in aging, is associated with disrupted homeostasis of neurotrophic factors in the hippocampus. The aim of this study was to investigate the effect of antibodies to glutamate on the content of neurotrophic factors (BDNF and GDNF) in the brain structures (prefrontal cortex and hippocampus) of aging mice, with intranasal administration of the neurotoxic fragment of β-amyloid protein Aβ25-35.

    Methods. The study was performed on C57BL/6 mice (n=43, weight 30.2 ± 1.5, age 12 months). The mice were divided into 4 groups: the 1st group (control) (n=11) received intranasal saline in a volume of 4 μl, the 2nd (n=10) – intranasal Aβ25-35 solution at a dose of 60 μg/kg in a volume of 4 μl, the 3rd (n=13) – simultaneously intranasally in different nostrils Aβ25-35 at a dose of 60 μg/kg in a volume of 4 μl and antibodies to glutamate at a dose of 250 μg/kg in a volume of 4 μl, and the 4th group (n=9) – antibodies to glutamate at a dose of 250 μg/kg in a volume of 4 μl. Intranasal administration of solutions was carried out daily for 14 days. Twenty-four hours after the last drug administration, mice were decapitated, and brain structures (prefrontal cortex and hippocampus) were removed at 4°C and subsequently stored at −85°C. BDNF and GDNF levels in the supernatant were determined by ELISA according to the protocol (Cloud-Clone Corp. test system) using an ImmunoChem-2100 ELISA reader at a wavelength of 450 nm. Interleukin concentrations were normalized per 1 mg of brain tissue.

     Results. Intranasal administration of the neurotoxic fragment Aβ25-35 to aging C57/BL6 mice at a dose of 60 μg/kg body weight for 14 days caused a decrease in BDNF levels in the prefrontal cortex. The GDNF content in the studied brain structures of mice administered Aβ25-35 did not differ from control values. Coadministration of Aβ25-35 with antibodies to glutamate led to a decrease in BDNF content in the prefrontal cortex by 46.2% and by 40.7% in the hippocampus compared to administration of Aβ25-35 alone. And the GDNF level decreased by 31.6% and 23.5% in the prefrontal cortex and hippocampus, respectively.

Conclusion. Long-term intranasal administration of the neurotoxic fragment Aβ25-35 to aging C57/BL6 mice caused a decrease in BDNF levels in the prefrontal cortex and had no effect on GDNF levels in the analyzed brain structures. Anti-glutamate antibodies, when co-administered with Aβ25-35, led to a significant decrease in BDNF and GDNF levels in both the prefrontal cortex and hippocampus of the mouse brain. A decrease in BDNF and GDNF levels in the analyzed brain structures also occurred with intranasal administration of anti-glutamate antibodies alone. Numerous studies have established a close interaction between the glutamate signaling systems and the neurotrophic factors BDNF and GDNF. Glutamate stimulates the production of BDNF and GDNF, which in turn enhance glutamate expression. It can be assumed that the decrease in the content of BDNF and GDNF in the brain structures of the experimental groups of mice is associated with a decrease in the activity of the glutamatergic system by antibodies to glutamate.