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Atorvastatin prevents endoplasmic reticulum stress-mediated apoptosis via the Nrf2/HO-1 signaling pathway in TBI mice.
Neurological Research 2023 January 23
BACKGROUND: Our present study evaluated the neuroprotection effects of atorvastatin by inhibiting TBI-induced ER stress, as well as the potential role of the Nrf2/HO-1 pathway in experimental TBI.
METHODS: First, the mice were divided into four groups:sham, TBI, TBI+Vehicle and TBI+atorvastatin groups. The mice received atorvastatin (10 mg/kg/day) through intragastric gavage once a day for 3 days before TBI. In addition, Nrf2 WT and Nrf2 knockout mice were randomly divided into four groups: Nrf2+/+ TBI, Nrf2+/+ TBI+atorvastatin, Nrf2-/- TBI, and Nrf2-/- TBI+atorvastatin groups. Several neurobehavioral parameters were assessed post-TBI using mNSS, brain edema and the rotarod test, and the brain was isolated for molecular and biochemical analysis conducted through TUNEL staining and western blotting. .
RESULTS: The results showed that atorvastatin treatment significantly improved neurological deficits, alleviated brain edema, and apoptosis caused by TBI. Western blotting analysis showed that atorvastatin significantly suppressed ER stress and its related apoptotic pathway after TBI, which may be associated with the further activation of the Nrf2/HO-1 pathway. However, compared with the Nrf2+/+ TBI+Vehicle group, Nrf2 deficiency further aggravated neurological deficits and promoted ER stress-mediated apoptosis induced by TBI. Interestingly, atorvastatin failed to improve neurological deficits but reversed apoptosis, and the loss of the beneficial properties of anti-ER stress in the Nrf2-/- TBI mice. .
CONCLUSIONS: The results indicated that atorvastatin improves the neurologic functions and protects the brain from injury in the Nrf2+/+ TBI mice, primarily by counteracting ER stress-mediated apoptosis, which may be achieved through the activation of the Nrf2/HO-1 signaling pathway.
METHODS: First, the mice were divided into four groups:sham, TBI, TBI+Vehicle and TBI+atorvastatin groups. The mice received atorvastatin (10 mg/kg/day) through intragastric gavage once a day for 3 days before TBI. In addition, Nrf2 WT and Nrf2 knockout mice were randomly divided into four groups: Nrf2+/+ TBI, Nrf2+/+ TBI+atorvastatin, Nrf2-/- TBI, and Nrf2-/- TBI+atorvastatin groups. Several neurobehavioral parameters were assessed post-TBI using mNSS, brain edema and the rotarod test, and the brain was isolated for molecular and biochemical analysis conducted through TUNEL staining and western blotting. .
RESULTS: The results showed that atorvastatin treatment significantly improved neurological deficits, alleviated brain edema, and apoptosis caused by TBI. Western blotting analysis showed that atorvastatin significantly suppressed ER stress and its related apoptotic pathway after TBI, which may be associated with the further activation of the Nrf2/HO-1 pathway. However, compared with the Nrf2+/+ TBI+Vehicle group, Nrf2 deficiency further aggravated neurological deficits and promoted ER stress-mediated apoptosis induced by TBI. Interestingly, atorvastatin failed to improve neurological deficits but reversed apoptosis, and the loss of the beneficial properties of anti-ER stress in the Nrf2-/- TBI mice. .
CONCLUSIONS: The results indicated that atorvastatin improves the neurologic functions and protects the brain from injury in the Nrf2+/+ TBI mice, primarily by counteracting ER stress-mediated apoptosis, which may be achieved through the activation of the Nrf2/HO-1 signaling pathway.
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