Dl-3-n-Butylphthalide Alleviates Demyelination and Improves Cognitive Function by Promoting Mitochondrial Dynamics in White Matter Lesions

Abstract

White matter lesions (WMLs) are a type of cerebrovascular disorder accompanied by demyelination and cognitive decline. Dl-3-n-butylphthalide (D1-NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases, although the function of DI-NBP on WML is still not clear. This study aims to investigate whether DI-NBP affects cognitive function and ameliorates demyelination in a model of WML. The bilateral carotid artery stenosis (BCAS) mouse model and in vitro brain slice cultures with low glucose and low oxygen (LGLO) treatment were adopted. The Dl-NBP was administered intragastrically for 28 days after BCAS or added at a dose of 50 μm for 48 h after LGLO. Spatial learning and memory were evaluated by an eight-arm radial maze. Demyelination was detected using a TEM. Mitochondrial dynamics were assessed by time-lapse imaging in the cultured brain slices. The function of the synapse was evaluated by the patch clamp technique. In BCAS mice, obvious demyelination and cognitive decline were observed, while both were significantly relieved by a high-dose D1-NBP treatment (100 mg/kg). Along with demyelination, mitochondrial accumulation in the axons was significantly increased in the BCAS mice model, but with the treatment of a high-dose D1-NBP, mitochondrial accumulation was mitigated, and the anterograde/retrograde transport of mitochondria was increased. Following the improved anterograde/retrograde transport of mitochondria, the synapse activity was significantly upregulated while the reactive oxygen species (ROS) generation was remarkably decreased in the cultured brain slices. In addition, we identified syntaphilin (SNPH) as the downstream target of D1-NBP. The overexpression of SNPH mediated the effects of D1-NBP in mitigating axonal mitochondrial accumulation. In conclusion, the D1-NBP treatment significantly relieved demyelination and improved spatial learning and memory in the WML model by promoting mitochondrial dynamics. These neuroprotective effects of D1-NBP were mediated by inhibiting the mitochondrial arching protein, SNPH, which provided a potential therapeutic target for WML.

Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

“…Drug concentrations were chosen based on previous reports. Some previous studies give us a clue on employing the experimental concentration of NBP ( 43 , 47 ). Combined with our pilot study, 50 mg/kg (low) and 100 mg/kg (high), the two comprehensive considerations were applied in the present study.…”

“…Dl-3-n-butylphthalide (NBP), has been approved for the therapy of acute ischemic stroke in patients since 2002 in China (36)(37)(38). Recently, studies have shown that NBP holds extensive pharmacological activities (39)(40)(41)(42)(43)(44)(45) and may exert potentially therapeutically beneficial effects on ischemia and vascular dementia; however, its precise mechanisms remain unclear. Evidences have suggested that NBP treatment could exert neuroprotective actions by enhancing anti-oxidation and attenuating mitochondrial dysfunction in models of ischemic stroke and could inhibit NLRP3 inflammasome activation via upregulating Nrf2 in AD models (45,46).…”

Demyelination of the Optic Nerve: An Underlying Factor in Glaucoma?

“…Enlarged and swollen mitochondria are observed in axons, accompanied by fading cristae in the mitochondria ( Coughlin et al, 2015 ; Thai et al, 2019 ). Mitochondrial dysfunction impairs mitochondrial transport along the axons and triggers necrosis of neurons ( Chandrasekaran et al, 2019 ; Feng et al, 2021 ). Some RGCs have an intact cell membrane with swollen organelles; some RGCs are severely damaged with disrupted cytoplasmic organelles and electron-dense clumped nuclear remnants distributed in the cytoplasm ( Narciso et al, 2001 ).…”

Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges

“… Classification Drug Mechanism Ref. Improve mitochondrial energy metabolism Vitamin E, vitamin C, alpha-lipoic acid, MitoQ, curcumin, astaxanthin, ginkgo biloba preparations Reduce superoxide radicals and scavenge hydrogen peroxide [ [83] , [84] , [85] , [86] ] Cyclosporin A mPTP inhibitor [ 87 ] Nicardipine Calcium channel blocker [ 64 ] sodium rutin Enhances the level of mitochondrial oxidative phosphorylation [ 89 ] Batrachocholine Improve mitochondrial ATP metabolism and modifying antioxidant proteins [ 90 ] Ginsenoside R b1 Inhibition of mitochondrial complex I activity [ 91 , 92 ] Balance the mitochondrial dynamics Mdivi-1 Repairs mitochondrial breakage and distribution defects [ 76 ] SS-31 Acts on the cardiolipin of mitochondrial inner membrane [ 93 , 94 ] Butylphthalide Balances the mitochondrial dynamics [ 95 ] Coordinate mitochondrial quality control Rapamycin, Torin1 and niclosamide Downregulation of the mTORC1 pathway [ 96 ] …”