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15 pages, 4235 KiB

Open AccessEditor’s ChoiceArticle

Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury

by Yaswanthi Yanamadala, Ritika Roy, Afrika Alake Williams, Navya Uppu, Audrey Yoonsun Kim, Mark A. DeCoster, Paul Kim and Teresa Ann Murray

Pharmaceutics 2024, 16(6), 774; https://doi.org/10.3390/pharmaceutics16060774 - 7 Jun 2024

Cited by 1 | Viewed by 1448

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is [...] Read more.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood–brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK’s ability to cross the blood–brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI. Full article

(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics, 2nd Edition)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Concentration-dependent uptake of fluorescently labeled peptides. Various concentrations of each peptide were incubated with BMVECs (10,000 per well) for 4 h with 20, 30, 50, and 75 µM of FITC-KAFAK (K20–K75), FITC-AIP-1 (A20–A75), and FITC-L57-AIP-1 (L20–L75). All three peptides exhibited concentration-dependent cellular uptake. However, intensity of internalized FITC-AIP-1 was significantly lower for all concentrations (<span class="html-italic">p</span> < 0.01). Even the highest concentration of FITC-AIP-1 had a significantly lower fluorescence intensity than the lowest concentration of KAFAK (A75 vs. K20, <span class="html-italic">p</span> < 0.01). While the intensity for FITC-L57-AIP-1 was higher than FITC-AIP-1 for each concentration level (<span class="html-italic">p</span> < 0.01), it was also significantly lower than concentration of FITC-KAFAK at each concentration level (<span class="html-italic">p</span> < 0.01). However, 75 µM FITC-L57-AIP-1 produced about the same fluorescence as 20 µM of KAFAK (downward arrows in figure). A total of 120 cells (<span class="html-italic">n</span> = 6 wells, 20 cells per well) were analyzed per concentration of each peptide using Image J software. Mean fluorescence intensity was normalized to that of control cells with no peptide (autofluorescence). Normalized fluorescence intensity was compared using ANOVA with a Bonferroni correction for multiple comparisons. (Data are represented as the mean ± 2 standard deviations).</p> Full article ">Figure 2
<p>The cell viability of BMVECs was measured using an ATP assay after 24 h of incubation with different peptide concentrations. FITC-AIP-1 (AIP) and FITC-L57-AIP-1 (L57) did not elicit cytotoxicity between 10–500 µM. KAFAK treatment from 10 to 100 µM did not significantly affect cell viability, and reduced cell viability was observed at 250 and 500 µM. Data are expressed as % of untreated control (mean ± SD, n = 3 wells/concentration of each peptide * <span class="html-italic">p</span> < 0.05).</p> Full article ">Figure 3
<p>Intranasal delivery of KAFAK to the brain. Mice were treated with 500 µM RITC-KAFAK. They were perfused four hours after treatment and brain sections were stained with DAPI to visualize cell nuclei. Images (<b>A</b>–<b>C</b>) are of a representative section showing that RITC-KAFAK permeated the olfactory bulb. Images (<b>D</b>–<b>F</b>) are of a representative section from the cerebral cortex. Images in the first column show fluorescently labeled KAFAK in the olfactory bulb (<b>A</b>) and cortex (<b>D</b>), with DAPI counterstaining shown in the second column (<b>B</b>,<b>E</b>). The KAFAK and DAPI images are merged in the third column (<b>C</b>,<b>F</b>). Scale bars are 100 µm.</p> Full article ">Figure 4
<p>Mean normalized rotarod performance on day 2, 5, and 7 for TBI-vehicle (TBI), Sham-vehicle (Sham), and TBI-KAFAK (KAFAK) groups. (<b>A</b>) shows the performance for all mice, while (<b>B</b>,<b>C</b>) represent the performance of female and male mice, respectively. (Mean ± SD, n = 8 for each group in (<b>A</b>) and n = 4 for each group in (<b>B</b>,<b>C</b>); * <span class="html-italic">p</span> < 0.05 Sham versus KAFAK and TBI, ** <span class="html-italic">p</span> < 0.01 Sham versus KAFAK and TBI, # <span class="html-italic">p</span> < 0.05 TBI versus KAFAK, ## <span class="html-italic">p</span> < 0.01 TBI versus KAFAK, †† <span class="html-italic">p</span> < 0.01 Sham versus TBI).</p> Full article ">Figure 5
<p>Mean mNSS for Sham-vehicle (Sham), TBI-KAFAK treated (KAFAK), and TBI-vehicle treated (TBI) groups on day 2, 5, and 7 (days after injury). Plots show mNSS results for (<b>A</b>) all mice, (<b>B</b>) female mice, and (<b>C</b>) male mice. (Data are expressed as the mean ± SD, n = 8 for each group in (<b>A</b>) and n = 4 for each group in (<b>B</b>,<b>C</b>); ** <span class="html-italic">p</span> < 0.01 Sham versus KAFAK and TBI, # <span class="html-italic">p</span> < 0.05 TBI versus KAFAK, ## <span class="html-italic">p</span> < 0.01 TBI versus KAFAK, † <span class="html-italic">p</span> < 0.05 Sham versus TBI, †† <span class="html-italic">p</span> < 0.01 Sham versus TBI).</p> Full article ">Figure 6
<p>KAFAK treatment rescued memory deficits associated with a moderate TBI. The mean discrimination index of the novel object recognition test for the TBI-vehicle group (TBI) was significantly lower than both Sham-vehicle (Sham) and TBI-KAFAK treated (KAFAK) groups seven days after injury (n = 8/group, mean of the discrimination index ± 2SD, ** <span class="html-italic">p</span> < 0.01 for TBI versus KAFAK and for TBI versus Sham).</p> Full article ">Figure 7
<p>IN administration of KAFAK (KAFAK IN) after TBI reduced levels of key proinflammatory cytokines, TNF, IL-1β, and IL-6, to sham levels. ELISA results show a significant increase in all three cytokines in injured, vehicle-treated mice (TBI-vehicle) versus sham-injured, vehicle treated mice (Sham). A significant reduction in TNF and IL-1β was observed in the KAFAK IN group versus the TBI-vehicle group. In contrast, no difference was observed between the TBI-vehicle group and the group that received an intraperitoneal delivery of KAFAK (KAFAK IP). (Data shown represent mean pg/mg tissue ± 2SD, n = 5/group, * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01).</p> Full article ">

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