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Published on: May 18, 2010
Minimum Effective Dose of Clemastine in a Mouse Model of Preterm White Matter Injury
Insights
The minimum effective dose of clemastine for treating preterm white matter injury (PWMI) in neonatal mice is 7.5 mg/kg/day. This finding is crucial for developing safe and effective clemastine treatments for neonates with PWMI.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Preterm white matter injury (PWMI) is a leading cause of brain damage in premature infants.
- PWMI is characterized by impaired oligodendrocyte differentiation, hindering central nervous system myelination.
- Clemastine has shown potential in promoting myelination in preclinical models, but its minimum effective dose (MED) in neonates is unknown.
Approach:
- Neonatal mice were exposed to hypoxia to model PWMI.
- Clemastine was administered orally at various doses (0.5, 2, 7.5, 10 mg/kg/day) to assess myelination.
- Immunohistochemistry and electron microscopy were used to determine the MED and evaluate myelination.
- Pharmacokinetic studies were conducted to analyze clemastine levels at the MED.
Key Points:
- The minimum effective dose (MED) of clemastine for rescuing hypoxia-induced hypomyelination in neonatal mice was determined to be 7.5 mg/kg/day.
- Pharmacokinetic analysis at the MED revealed a Cmax of 44.0 ng/mL, t1/2 of 4.6 hours, and AUC24 of 280.1 ng*hr/mL.
- These findings establish a critical dose for future clinical trials in neonates with PWMI.
Conclusions:
- A dose of 7.5 mg/kg/day of clemastine effectively promotes myelination in a murine model of preterm white matter injury.
- Achieving myelination-promoting exposures with oral clemastine in neonates with PWMI is feasible.
- This study provides essential data for designing clinical trials to evaluate clemastine as a treatment for neonatal brain injury.
Background:
Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification if the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day.
Methods:
Mouse pups were exposed to normoxia or hypoxia (10% FiO 2 ) from postnatal day 3 (P3) through P10. Vehicle or clemastine fumarate at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given orally to hypoxia-exposed pups. At P14, myelination was assessed by immunohistochemistry and electron microscopy to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment.
Results:
Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C max 44.0 ng/mL, t 1/2 4.6 hours, and AUC 24 280.1 ng*hr/mL.
Conclusion:
Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI.
Key Points:
Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates.Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment.The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials.We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.
