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Serum levels of TG, TC, and LDL-c were lower in ApoE-/- HD+S mice than in ApoE-/- HD mice. Immunohistochemistry, real-time PCR, and immunoblotting showed increased levels of GFAP in the ApoE-/- HD group. Immunoblotting revealed increased levels of NLRP3, IL-18, caspase-1, Bax, Bcl-2, and p-ERK in the ApoE-/- HD group; however, they were significantly suppressed in the ApoE-/- HD+S group. Therefore, exercise has protective effects against neuronal injury caused by hyperlipidemia. There is still no effective treatment of neuropathic pain