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BMC Neurology

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Open Access 01-12-2022 | Epilepsy | Research

DL-3-n-butylphthalide promotes hippocampal neurogenesis and reduces mossy fiber sprouting in chronic temporal lobe epilepsy rats

Authors: Shanshan Zhao, Fangxi Liu, Wei Shi, Jialu Wang, Zhike Zhou, Xiaoqian Zhang

Published in: BMC Neurology | Issue 1/2022

Abstract

Background

A decrease in hippocampal neurogenesis is considered an important cause of cognitive impairment, while changes in mossy fiber sprouting are closely related to development of spontaneous recurrent seizures in chronic temporal lobe epilepsy (TLE). Racemic l-3-n-butylphthalide (DL-NBP) can alleviate cognitive impairment in ischemic stroke and Alzheimer’s disease by promoting neurogenesis. DL-NBP treatment can also improve cognitive function and reduce seizure incidence in chronic epileptic mice. However, the mechanisms of action of DL-NBP remain unclear. The aim of the present study was to examine the effects of DL-NBP on mossy fiber sprouting, hippocampal neurogenesis, spontaneous epileptic seizures, and cognitive functioning in the chronic phase of TLE.

Methods

Nissl staining was used to evaluate hippocampal injury, while immunofluorescent staining was used to analyze hippocampal neurogenesis. The duration of spontaneous seizures was measured by electroencephalography. The Morris water maze was used to evaluate cognitive function. Timm staining was used to assess mossy fiber sprouting.

Results

TLE animals showed reduced proliferation of newborn neurons, cognitive dysfunction, and spontaneous seizures. Treatment with DL-NBP after TLE increased the proliferation and survival of newborn neurons in the dentate gyrus, reversed the neural loss in the hippocampus, alleviated cognitive impairments, and decreased mossy fiber sprouting and long-term spontaneous seizure activity.

Conclusions

We provided pathophysiological and morphological evidence that DL-NBP might be a useful therapeutic for the treatment of TLE.

Helmstaedter C, Elger CE. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease? Brain. 2009;132(Pt 10):2822–30. https://doi.org/10.1093/brain/awp182.CrossRefPubMed

Tavakoli M, Barekatain M, Doust HT, Molavi H, Nouri RK, Moradi A, et al. Cognitive impairments in patients with intractable temporal lobe epilepsy. J Res Med Sci. 2011;16(11):1466–72.PubMedPubMedCentral

Sutula TP, Hagen J, Pitkänen A. Do epileptic seizures damage the brain? Curr Opin Neurol. 2003;16(2):189–95. https://doi.org/10.1097/01.wco.0000063770.15877.bc.CrossRefPubMed

Holmes M, Flaminio Z, Vardhan M, Xu F, Li X, Devinsky O, et al. Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia. 2020;61(12):2619–28. https://doi.org/10.1111/epi.16744.CrossRefPubMed

Zhao Y, Liu D, Li J, Zhang X, Wang X. L-NBP, a multiple growth factor activator, attenuates ischemic neuronal impairments possibly through promoting neuritogenesis. Neurochem Int. 2019;124:94–105. https://doi.org/10.1016/j.neuint.2019.01.002.CrossRefPubMed

Zhao Y, Lee JH, Chen D, Gu X, Caslin A, Li J, et al. DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice. Neurochem Int. 2017;111:82–92. https://doi.org/10.1016/j.neuint.2017.03.017.CrossRefPubMedPubMedCentral

Lei H, Zhang Y, Huang L, Xu S, Li J, Yang L, et al. L-3-n-butylphthalide regulates proliferation, migration, and differentiation of neural stem cell in vitro and promotes neurogenesis in APP/PS1 mouse model by regulating BDNF/TrkB/CREB/Akt pathway. Neurotox Res. 2018;34(3):477–88. https://doi.org/10.1007/s12640-018-9905-3.CrossRefPubMed

Li W, Wei D, Lin J, Liang J, Xie X, Song K, et al. Dl-3-n-butylphthalide reduces cognitive impairment induced by chronic cerebral hypoperfusion through GDNF/GFRα1/ret signaling preventing hippocampal neuron apoptosis. Front Cell Neurosci. 2019;13:351. https://doi.org/10.3389/fncel.2019.00351.CrossRefPubMedPubMedCentral

Ye X, Rong Z, Li Y, Wang X, Cheng B, Cheng Y, et al. Protective role of L-3-n-butylphthalide in cognitive function and dysthymic disorders in mouse with chronic epilepsy. Front Pharmacol. 2018;9:734. https://doi.org/10.3389/fphar.2018.00734.CrossRefPubMedPubMedCentral

10.

Song C, Xu W, Zhang X, Wang S, Zhu G, Xiao T, et al. CXCR4 antagonist AMD3100 suppresses the long-term abnormal structural changes of newborn neurons in the intraventricular kainic acid model of epilepsy. Mol Neurobiol. 2016;53(3):1518–32. https://doi.org/10.1007/s12035-015-9102-9.CrossRefPubMed

11.

Hattiangady B, Shetty AK. Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy. Epilepsia. 2008;49(Suppl 5):26–41. https://doi.org/10.1111/j.1528-1167.2008.01635.x.CrossRefPubMedPubMedCentral

12.

Hattiangady B, Rao MS, Shetty AK. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis. 2004;17(3):473–90. https://doi.org/10.1016/j.nbd.2004.08.008.CrossRefPubMed

13.

Zhong Q, Ren BX, Tang FR. Neurogenesis in the hippocampus of patients with temporal lobe epilepsy. Curr Neurol Neurosci Rep. 2016;16(2):20. https://doi.org/10.1007/s11910-015-0616-3.CrossRefPubMed

14.

Hattiangady B, Shetty AK. Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy. Hippocampus. 2010;20(1):97–112. https://doi.org/10.1002/hipo.20594.CrossRefPubMedPubMedCentral

15.

Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci. 2006;9(6):723–7. https://doi.org/10.1038/nn1707.CrossRefPubMed

16.

Nickels KC, Zaccariello MJ, Hamiwka LD, Wirrell EC. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat Rev Neurol. 2016;12(8):465–76. https://doi.org/10.1038/nrneurol.2016.98.CrossRefPubMed

17.

Xu J, Huai Y, Meng N, Dong Y, Liu Z, Qi Q, et al. L-3-n-butylphthalide activates Akt/mTOR signaling, inhibits neuronal apoptosis and autophagy and improves cognitive impairment in mice with repeated cerebral ischemia-reperfusion injury. Neurochem Res. 2017;42(10):2968–81. https://doi.org/10.1007/s11064-017-2328-3.CrossRefPubMed

18.

Wang BN, Wu CB, Chen ZM, Zheng PP, Liu YQ, Xiong J, et al. DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress. Acta Pharmacol Sin. 2021;42(3):347–60. https://doi.org/10.1038/s41401-020-00583-3.CrossRefPubMed

19.

Cheng X, Wang H, Liu C, Zhong S, Niu X, Zhang X, et al. Dl-3-n-butylphthalide promotes remyelination process in cerebral white matter in rats subjected to ischemic stroke. Brain Res. 2019;1717:167–75. https://doi.org/10.1016/j.brainres.2019.03.017.CrossRefPubMed

20.

Lv C, Ma Q, Han B, Li J, Geng Y, Zhang X, et al. Long-term DL-3-n-butylphthalide treatment alleviates cognitive impairment correlate with improving synaptic plasticity in SAMP8 mice. Front Aging Neurosci. 2018;10:200. https://doi.org/10.3389/fnagi.2018.00200.CrossRefPubMedPubMedCentral

21.

Yang LC, Li J, Xu SF, Cai J, Lei H, Liu DM, et al. L-3-n-butylphthalide promotes neurogenesis and neuroplasticity in cerebral ischemic rats. CNS Neurosci Ther. 2015;21(9):733–41. https://doi.org/10.1111/cns.12438.CrossRefPubMedPubMedCentral

22.

Witt JA, Helmstaedter C. Cognition in epilepsy: current clinical issues of interest. Curr Opin Neurol. 2017;30(2):174–9. https://doi.org/10.1097/WCO.0000000000000430.CrossRefPubMed

23.

Jiao Y, Nadler JV. Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol. 2007;205(2):569–82. https://doi.org/10.1016/j.expneurol.2007.03.025.CrossRefPubMedPubMedCentral

24.

Freiman TM, Häussler U, Zentner J, Doostkam S, Beck J, Scheiwe C, et al. Mossy fiber sprouting into the hippocampal region CA2 in patients with temporal lobe epilepsy. Hippocampus. 2021;31(6):580–92. https://doi.org/10.1002/hipo.23323.CrossRefPubMed

25.

Vazifehkhah S, Ali MK, Babae JF, Hashemi P, Alireza MS, Nikbakht F. Evaluation of the ameliorative effects of oral administration of metformin on epileptogenesis in the temporal lobe epilepsy model in rats. Life Sci. 2020;257:118066. https://doi.org/10.1016/j.lfs.2020.118066.CrossRefPubMed

26.

Feng Y, Duan C, Luo Z, Xiao W, Tian F. Silencing miR-20a-5p inhibits axonal growth and neuronal branching and prevents epileptogenesis through RGMa-RhoA-mediated synaptic plasticity. J Cell Mol Med. 2020;24(18):10573–88. https://doi.org/10.1111/jcmm.15677.CrossRefPubMedPubMedCentral

27.

Botterill JJ, Lu YL, LaFrancois JJ, Bernstein HL, Alcantara-Gonzalez D, Jain S, et al. An excitatory and epileptogenic effect of dentate gyrus mossy cells in a mouse model of epilepsy. Cell Rep. 2019;29(9):2875–2889.e6. https://doi.org/10.1016/j.celrep.2019.10.100.CrossRefPubMedPubMedCentral

Title: DL-3-n-butylphthalide promotes hippocampal neurogenesis and reduces mossy fiber sprouting in chronic temporal lobe epilepsy rats
Authors: Shanshan Zhao
Fangxi Liu
Wei Shi
Jialu Wang
Zhike Zhou
Xiaoqian Zhang
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Epilepsy
Published in: BMC Neurology / Issue 1/2022
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-021-02516-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

DL-3-n-butylphthalide promotes hippocampal neurogenesis and reduces mossy fiber sprouting in chronic temporal lobe epilepsy rats

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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