ABSTRACT
Objective:
To observe the effect of α-
lipoic acid(ALA) on the intracerebroventricular
injection(icv) of
streptozotocin(STZ)-induced
spatial learning memory impairments in
rats and the underlying molecular mechanisms.
Methods:
Forty-five
male SD
rats were assigned into 3
groups, control group, icv-STZ group and icv-STZ+ ALA group, 15
rats each. STZ was dissolved in artificial
cerebrospinal fluid then injected into the
lateral ventricles of the
rat by using stereotaxic
device. ALA was administrated by gavage after STZ
injection. The
spatial learning memory was examined by using
Morris water maze test after 4 weeks of
treatment.
Immunohistochemistry was performed to detect the number of
microglia and
astrocytes,
electron microscopy was applied to detect mitochondrial integrity,
Western blotting was used to detect the
protein expression levels, and the changes of
lipid peroxidation and
redox system were examined by kit.
Results:
Spatial learning memory was impaired in
rats after 4 weeks of STZ
injection, and ALA
treatment ameliorated STZ-induced
cognitive dysfunction in
rats.
Iron concentration,
lipid peroxidation,
neuroinflammation, Tau hyperphosphorylated were enhanced markedly after STZ
injection, along with and the activation of MAPK and
GSK-3β, which were ameliorated by ALA. Further examination revealed that STZ activated the JAK2/STAT3 pathway and transcriptionally inhibited the expression of
peroxidase GPX. Inhibition of STAT3 activity can block STZ-induced
downregulation of GPX4 and Tau hyperphosphorylation.
Conclusion:
ALA ameliorated STZ-induced
spatial learning memory impairments in
rats via deactivation of JAK2/STAT3 pathway, restored GPX4
protein level, resulting in chelating
iron, improving mitochondrial function, balancing the
redox system, ameliorating Tau hyperphosphorylation and
neuroinflammation.
