Neuroprotective Effect of Dichloromethane Extraction From Piper nigrum L. and Piper longum L. on Permanent Focal Cerebral Ischemia Injury in Rats

J Stroke Cerebrovasc Dis. 2019 Mar;28(3):751-760. doi: 10.1016/j.jstrokecerebrovasdis.2018.11.018. Epub 2018 Dec 8.

Abstract

Background: Piper nigrum L. and Piper longum L. consist a classic formula in traditional Chinese Hui medicine and are widely used in treatment of stroke. To examine the therapeutic effect of neuron injury after apoplexy, we used a permanent middle cerebral artery occlusion model in rats to investigate the effects of dichloromethane fraction (DF) of Piper nigrum L. and Piper longum L.

Materials and methods: After subjecting the rats to permanent middle cerebral artery occlusion, DF (100 and 200 mg/kg) were administered for 14 days. Neurological deficits and the degree of cerebral tissue injury was detected by 2,3,5-Triphenyltetrazolium Chloride Staining Hematoxylin and eosin staining and Nissl staining. Postsynaptic density protein 95 (PSD-95), synapsin-I (syn-I), and α-synuclein (α-syn) were stained by immunohistochemistry. PSD-95, Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMK II), phosphorylated CaMK II (p-CaMK II), CaM, N-methyl D-aspartate receptor subtype 2B (NR2B) expression were detected by Western blot. Meanwhile, phytochemical profile of DF was determined through ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS).

Results: DF alleviated neurological deficits and markedly prevented ischemia-induced cellular damage. Immunohistochemical micrographs revealed that PSD-95 and syn-I proteins increased, and α-syn presented reduced expression in brain samples from the sham group. Western blot analyses revealed that the model group exhibited a noticeable reduction in PSD-95, p-CaMK II, CaM, and NR2B. The DF-treated model group exhibited increased PSD-95, p-CaMK II, CaM, and NR2B. UPLC-Q-TOF/MS analysis revealed eight main components of DF, of which piperine accounted for the largest proportion.

Keywords: Permanent middle cerebral artery occlusion; UPLC-Q-TOF/MS; motor dysfunction; neuroprotective effects.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Calmodulin / metabolism
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Infarction, Middle Cerebral Artery / prevention & control*
  • Male
  • Methylene Chloride / chemistry*
  • Motor Activity / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / isolation & purification
  • Neuroprotective Agents / pharmacology*
  • Phosphorylation
  • Piper nigrum* / chemistry
  • Piper* / chemistry
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology*
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Solvents / chemistry*
  • Synapsins / metabolism
  • alpha-Synuclein / metabolism

Substances

  • Calmodulin
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • NR2B NMDA receptor
  • Neuroprotective Agents
  • Plant Extracts
  • Receptors, N-Methyl-D-Aspartate
  • Snca protein, rat
  • Solvents
  • Synapsins
  • alpha-Synuclein
  • Methylene Chloride
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2