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Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form
to different brain regions as a model for enzyme therapy in the CNS
#MMPMID26688469
Appu AP
; Arun P
; Krishnan JKS
; Moffett JR
; Namboodiri AMA
J Neurosci Methods
2016[Feb]; 259
(?): 129-134
PMID26688469
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BACKGROUND: The blood brain barrier (BBB) is critical for maintaining central
nervous system (CNS) homeostasis by restricting entry of potentially toxic
substances. However, the BBB is a major obstacle in the treatment of
neurotoxicity and neurological disorders due to the restrictive nature of the
barrier to many medications. Intranasal delivery of active enzymes to the brain
has therapeutic potential for the treatment of numerous CNS enzyme deficiency
disorders and CNS toxicity caused by chemical threat agents. NEW METHOD: The aim
of this work is to provide a sensitive model system for analyzing the rapid
delivery of active enzymes into various regions of the brain with therapeutic
bioavailability. RESULTS: We tested intranasal delivery of chloramphenicol
acetyltransferase (CAT), a relatively large (75kD) enzyme, in its active form
into different regions of the brain. CAT was delivered intranasally to
anaesthetized rats and enzyme activity was measured in different regions using a
highly specific High Performance Thin Layer Chromatography (HP-TLC)-radiometry
coupled assay. Active enzyme reached all examined areas of the brain within 15min
(the earliest time point tested). In addition, the yield of enzyme activity in
the brain was almost doubled in the brains of rats pre-treated with matrix
metalloproteinase-9 (MMP-9). COMPARISON WITH EXISTING METHOD (S): Intranasal
administration of active enzymes in conjunction with MMP-9 to the CNS is both
rapid and effective. CONCLUSION: The present results suggest that intranasal
enzyme therapy is a promising method for counteracting CNS chemical threat
poisoning, as well as for treating CNS enzyme deficiency disorders.
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