PMID- 30319425
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 9
DP  - 2018
TI  - Age-Dependent Anti-migraine Effects of Valproic Acid and Topiramate in Rats.
PG  - 1095
LID - 10.3389/fphar.2018.01095 [doi]
LID - 1095
AB  - Background: Valproic acid (VPA) and topiramate (TPM), initially developed as 
      antiepileptics, are approved for migraine prophylaxis in adults but not children. 
      The differences in their antimigraine mechanism(s) by age remain unclear. 
      Methods: A migraine model induced by intra-cisternal (i.c.) capsaicin 
      instillation in pediatric (4-5 weeks) and adult (8-9 weeks) rats was pretreated 
      with VPA (30, 100 mg/kg) or TPM (10, 30, 100 mg/kg). Noxious meningeal 
      stimulation by the irritant capsaicin triggered trigeminovascular system (TGVS) 
      activation mimicking migraine condition, which were assessed peripherally by the 
      depletion of calcitonin gene-related peptide (CGRP) in sensory nerve fibers of 
      the dura mater, the increased CGRP immunoreactivity at trigeminal ganglia (TG) 
      and centrally by the number of c-Fos-immunoreactive (c-Fos-ir) neurons in the 
      trigeminocervical complex (TCC). Peripherally, CGRP released from dural sensory 
      nerve terminals of TG triggered pain signal transmission in the primary afferent 
      of trigeminal nerve, which in turn caused central sensitization of the TGVS due 
      to TCC activation and hence contributed to migraine. Results: In the VPA-treated 
      group, the central responsiveness expressed by reducing the number of c-Fos-ir 
      neurons, which had been increased by i.c. capsaicin, was significant in 
      pediatric, but not adult, rats. Inversely, VPA was effective in peripheral 
      inhibition of elevated CGRP immunoreactivity in the TG and CGRP depletion in the 
      dura mater of adult, but not pediatric, rats. In TPM group, the central 
      responsiveness was significant in both adult and pediatric groups. Peripherally, 
      TPM significantly inhibited capsaicin-induced CGRP expression of TG in adult, but 
      not pediatric, rats. Interestingly, the capsaicin-induced depletion of CGRP in 
      dura was significantly rescued by TPM at high doses in adults, but at low dose in 
      pediatric group. Conclusion: These results suggest VPA exerted peripheral 
      inhibition in adult, but central suppression in pediatric migraine-rats. In 
      contrast, TPM involves both central and peripheral inhibition of migraine with an 
      optimal therapeutic window in both ages. These findings may clarify the 
      age-dependent anti-migraine mechanism of VPA and TPM, which may guide the 
      development of new pediatric anti-migraine drugs in the future.
FAU - Huang, Pokai
AU  - Huang P
AD  - Department of Pediatrics, E-da Dachang Hospital, Kaohsiung, Taiwan.
FAU - Kuo, Ping-Hung
AU  - Kuo PH
AD  - Department of Internal Medicine, National Taiwan University Hospital, College of 
      Medicine, National Taiwan University, Taipei, Taiwan.
FAU - Lee, Ming Tatt
AU  - Lee MT
AD  - Graduate Institute of Brain and Mind Sciences, College of Medicine, National 
      Taiwan University, Taipei, Taiwan.
AD  - Graduate Institute of Pharmacology, College of Medicine, National Taiwan 
      University, Taipei, Taiwan.
AD  - Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia.
FAU - Chiou, Lih-Chu
AU  - Chiou LC
AD  - Graduate Institute of Brain and Mind Sciences, College of Medicine, National 
      Taiwan University, Taipei, Taiwan.
AD  - Graduate Institute of Pharmacology, College of Medicine, National Taiwan 
      University, Taipei, Taiwan.
AD  - Graduate Institute of Acupuncture Science, China Medical University, Taichung, 
      Taiwan.
FAU - Fan, Pi-Chuan
AU  - Fan PC
AD  - Department of Pediatrics, National Taiwan University Hospital, College of 
      Medicine, National Taiwan University, Taipei, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20180925
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC6167431
OTO - NOTNLM
OT  - CGRP
OT  - age difference
OT  - migraine
OT  - topiramate
OT  - valproic acid
EDAT- 2018/10/16 06:00
MHDA- 2018/10/16 06:01
PMCR- 2018/09/25
CRDT- 2018/10/16 06:00
PHST- 2018/04/25 00:00 [received]
PHST- 2018/09/07 00:00 [accepted]
PHST- 2018/10/16 06:00 [entrez]
PHST- 2018/10/16 06:00 [pubmed]
PHST- 2018/10/16 06:01 [medline]
PHST- 2018/09/25 00:00 [pmc-release]
AID - 10.3389/fphar.2018.01095 [doi]
PST - epublish
SO  - Front Pharmacol. 2018 Sep 25;9:1095. doi: 10.3389/fphar.2018.01095. eCollection 
      2018.