Uptake of the antisecretory factor peptide AF-16 in rat blood and cerebrospinal fluid and effects on elevated intracranial pressure

Abstract

BackgroundAF-16 is a 16-amino-acid-long peptide derived from the amino-terminal part of the endogenous protein, antisecretory factor (AF). AF-16 in vivo has been shown to regulate dysfunctions in the water and ion transport system under various pathological conditions and also to counteract experimentally increased tissue pressure.MethodsRats were subjected to a cryogenic brain injury in order to increase the intracranial pressure (ICP). The distribution of AF-16 in blood and CSF after intravenous or intranasal administration was determined in injured and control rats. ICP was monitored in freely moving, awake rats, by means of an epidural pressure transducer catheter connected to a wireless device placed subcutaneously on the skull. The continuous ICP registrations were achieved by means of telemetry.ResultsIntranasal administration of AF-16 resulted in a significantly higher CSF concentrations of AF-16 in injured than in control rats, 1.3 versus 0.6 ng/ml, whereas no difference between injured and control rats was seen when AF-16 was given intravenously. Rats subjected to cryogenic brain injury developed gradually increasing ICP levels. Intranasal administration of AF-16 suppressed the increased ICP to normal values within 30 min.ConclusionOptimal AF-16 concentrations in CSF are achieved after intranasal administration in rats subjected to a cryogenic brain injury. The ability of AF-16 to suppress an increased ICP was manifested.

Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat

“…High molecular weight proteins, such as horseradish peroxidase, and peptides, such as insulin-like growth factor I (IGF-I) and insulin, have been conclusively observed to be taken up after nasal instillation, transported to the olfactory bulb and then further throughout the brain including into the CSF ( 29 – 32 ). The peptide AF-16 used in the present report reaches high concentration in the CSF after intranasal instillation ( 16 ) and the beneficial effects imply that AF-16 reached the brain parenchyma and retained its biological activity after the intranasal instillation also in the present study. These results are in agreement with those achieved in previous studies where intranasal administration of AF-16 attenuated the rise in ICP and reduced the high mortality in herpes simplex type I encephalitis in rats ( 18 ).…”

“…The treatment peptide AF16 or the scrambled inactive peptide (hereafter named Scramble) were instilled intranasally by briefly sedating the rats with isoflurane (4% in air for induction and 1% in air through a nosecone for maintaining sedation) and gently injecting 25 µl per nostril of isotonic saline solution with scramble or AF-16 peptide (2 mg/ml), as previously described ( 15 , 16 ). The first treatment was administered 30 min after mFPI or sham injury and at a corresponding time point for naïve animals.…”

“…However, AF has not been shown to influence fluid distribution in normal tissue, nor exert any toxicity under normal conditions ( 14 – 17 ). A 16-peptide fragment, named AF-16, was developed as a pharmacological compound for intranasal administration, showing positive results on brain edema formation in both cold lesion injury ( 15 , 16 ) and experimental encephalitis, in the latter study significantly improving survival due to reduced ICP without influencing the inflammatory response ( 18 ). Using the intranasal route of administration, AF-16 was observed to enter the brain and was detected in the cerebrospinal fluid [CSF ( 16 )].…”

“…A 16-peptide fragment, named AF-16, was developed as a pharmacological compound for intranasal administration, showing positive results on brain edema formation in both cold lesion injury ( 15 , 16 ) and experimental encephalitis, in the latter study significantly improving survival due to reduced ICP without influencing the inflammatory response ( 18 ). Using the intranasal route of administration, AF-16 was observed to enter the brain and was detected in the cerebrospinal fluid [CSF ( 16 )]. In the present study, we used a clinically relevant DAI model, the midline fluid percussion brain injury (mFPI), in rats and hypothesized that intranasal AF-16 could attenuate the traumatically induced cerebral edema, behavioral impairment, and various TBI-induced histological factors.…”

High doses of Antisecretory Factor stop diarrhea fast without recurrence for six weeks post treatment

“…Thus, a detailed biological mechanism of action in vivo of the various AF peptides remains to be described. Experimental studies demonstrate that the AF peptide, AF-16, suppresses increased intracranial pressure in rats, and also decreases a high intratumoral pressure in rat mammary cancer (Al-Olama et al, 2015,2011. The registered suppression of the increased intracranial as well as intratumoral pressure is noted within minutes.…”