title: Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction.
abstract: BACKGROUND
  The therapeutic potential of berberine has been well documented in various neurological problems. However, the neurological mechanism of berberine remains untapped in the light of its P-glycoprotein (P-gp)-mediated gut efflux properties responsible for reduced bioavailability. Verapamil, a well known L-type calcium channel blocker, has additional inhibitory activity against P-gp efflux pump. Thus, there is a strong scientific rationale to explore the interaction of berberine with verapamil as a possible neuroprotective strategy.
  
  
  OBJECTIVE
  The present study was designed to evaluate the effect of berberine, verapamil, and their combination on behavioral alterations, oxidative stress, mitochondrial dysfunction, neuroinflammation, and histopathological modifications in intracerebroventricular streptozocin (ICV-STZ)-induced sporadic dementia of Alzheimer's type in rats.
  
  
  METHODS
  Single bilateral ICV-STZ (3 mg/kg) administration was used as an experimental model of sporadic dementia of Alzheimer's type.
  
  
  RESULTS
  Berberine (25, 50, and 100 mg/kg, oral gavage) or verapamil (2.5 and 5 mg/kg, intraperitoneally) were used as treatment drugs, and memantine (5 mg/kg, intraperitoneally) was used as a standard. Berberine and verapamil significantly attenuated behavioral, biochemical, cellular, and histological alterations, suggesting their neuroprotective potential. Further, treatment of berberine (25 and 50 mg/kg) with verapamil (2.5 and 5.0 mg/kg) combinations respectively significantly potentiated their neuroprotective effect which was significant as compared to their effect per se in ICV-STZ-treated animals.
  
  
  CONCLUSIONS
  The augmentative outcome of verapamil on the neuroprotective effect of berberine can be speculated due to the inhibition of P-gp efflux mechanism and the prevention of calcium homeostasis alteration. Additionally, anti-inflammatory and antioxidant effects of both berberine and verapamil could also contribute in their protective effect.
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India. kumaruips@yahoo.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
authors.lastname: Ekavali
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
authors.forename: Jitendriya
authors.initials: J
authors.lastname: Mishra
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
authors.forename: Kanwaljit
authors.initials: K
authors.lastname: Chopra
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Dhull
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001599:Berberine / Q000008:administration & dosage*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000633:toxicity*; D014700:Verapamil / Q000008:administration & dosage*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018696:Neuroprotective Agents; D001599:Berberine; D013311:Streptozocin; D014700:Verapamil
keywords: Alzheimer; Berberine; Cognition; Neuroinflammation; Neuroprotection; Oxidative stress; P-glycoprotein; Streptozotocin; Verapamil