Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms

Marine Jequier Gygax, Brian D. Klein, H. Steve White, Mimi Kim, Aristea S. Galanopoulou

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4. mg/kg) or vehicle. Video monitoring for spasms included a 1. h pre-injection period, followed by 5. h of recording post-injection, and two 2. h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2. h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4. h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n= 11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4. h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7. mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms.

Original languageEnglish (US)
Pages (from-to)98-108
Number of pages11
JournalEpilepsy Research
Volume108
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Galanin
Infantile Spasms
Spasm
Messenger RNA
Injections
Cerebral Cortex
Receptor, Galanin, Type 1
Reflex
Blood Glucose
Hippocampus
Fenclonine
NAX 5055
Oximetry
Vital Signs
Brain Diseases
Doxorubicin
Reverse Transcription
Sprague Dawley Rats
Lipopolysaccharides
Pulse

Keywords

  • Antibody
  • Antiepileptic
  • Cerebral cortex
  • Galanin receptor
  • Glucose
  • Neurodevelopmental reflexes

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms. / Jequier Gygax, Marine; Klein, Brian D.; White, H. Steve; Kim, Mimi; Galanopoulou, Aristea S.

In: Epilepsy Research, Vol. 108, No. 1, 01.2014, p. 98-108.

Research output: Contribution to journalArticle

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AU - Galanopoulou, Aristea S.

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AB - Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4. mg/kg) or vehicle. Video monitoring for spasms included a 1. h pre-injection period, followed by 5. h of recording post-injection, and two 2. h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2. h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4. h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n= 11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4. h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7. mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms.

KW - Antibody

KW - Antiepileptic

KW - Cerebral cortex

KW - Galanin receptor

KW - Glucose

KW - Neurodevelopmental reflexes

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