Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice
<b>Background/Objectives</b>: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal adminis...
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| author | Hiroshi Nango Ai Takahashi Naoto Suzuki Takumi Kurano Saia Sakamoto Taiki Nagatomo Toyofumi Suzuki Takanori Kanazawa Yasuhiro Kosuge Hiroko Miyagishi |
| author_facet | Hiroshi Nango Ai Takahashi Naoto Suzuki Takumi Kurano Saia Sakamoto Taiki Nagatomo Toyofumi Suzuki Takanori Kanazawa Yasuhiro Kosuge Hiroko Miyagishi |
| author_sort | Hiroshi Nango |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of <i>N</i>-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) for neuropathic pain. <b>Methods</b>: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Mechanical allodynia was assessed using the von Frey test on days 11–14 post-ligation. NAC or NAC/PPT was intranasally administered after pain onset. Western blotting and immunohistochemistry were conducted to evaluate ionized calcium-binding adapter molecule 1 (Iba-1) expression and microglial activation in the spinal cord. <b>Results</b>: Mechanical allodynia was exacerbated 11 days after the ligation in PSNL mice. The intranasal administration of NAC alone prevented allodynia exacerbation but failed to provide a therapeutic effect against allodynia in PSNL mice. In contrast, NAC/PPT administration ameliorated PSNL-induced tactile allodynia, with maximum efficacy seen 13 and 14 days after ligation. Western blotting demonstrated that Iba-1 levels tended to increase in PSNL mice compared to controls. This trend of increased Iba-1 levels in PSNL mice was attenuated by the administration of NAC/PPT, but not by NAC alone. Immunohistochemistry revealed an increased number of Iba-1-stained microglia in the ipsilateral spinal cord of PSNL mice, which were significantly suppressed by the administration of NAC/PPT. <b>Conclusions</b>: These results suggest that the post-onset intranasal administration of NAC/PPT ameliorates mechanical allodynia by suppressing microglia induction and that intranasal delivery with PEG-PCL-Tat might be a useful tool for the pharmacological management of neuropathic pain. |
| format | Article |
| id | doaj-art-335a9efe0983428bad789e846f840132 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Pharmaceutics |
| spelling | doaj-art-335a9efe0983428bad789e846f8401322025-01-24T13:45:41ZengMDPI AGPharmaceutics1999-49232025-01-011714410.3390/pharmaceutics17010044Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation MiceHiroshi Nango0Ai Takahashi1Naoto Suzuki2Takumi Kurano3Saia Sakamoto4Taiki Nagatomo5Toyofumi Suzuki6Takanori Kanazawa7Yasuhiro Kosuge8Hiroko Miyagishi9Laboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanDepartment of Clinical Pharmacology, Graduate School of Biomedical Sciences, Tokushima University, 1-78-1 Shoumachi, Tokushima 770-8505, JapanLaboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, JapanLaboratory of Pharmacology, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi 274-8555, Japan<b>Background/Objectives</b>: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of <i>N</i>-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) for neuropathic pain. <b>Methods</b>: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Mechanical allodynia was assessed using the von Frey test on days 11–14 post-ligation. NAC or NAC/PPT was intranasally administered after pain onset. Western blotting and immunohistochemistry were conducted to evaluate ionized calcium-binding adapter molecule 1 (Iba-1) expression and microglial activation in the spinal cord. <b>Results</b>: Mechanical allodynia was exacerbated 11 days after the ligation in PSNL mice. The intranasal administration of NAC alone prevented allodynia exacerbation but failed to provide a therapeutic effect against allodynia in PSNL mice. In contrast, NAC/PPT administration ameliorated PSNL-induced tactile allodynia, with maximum efficacy seen 13 and 14 days after ligation. Western blotting demonstrated that Iba-1 levels tended to increase in PSNL mice compared to controls. This trend of increased Iba-1 levels in PSNL mice was attenuated by the administration of NAC/PPT, but not by NAC alone. Immunohistochemistry revealed an increased number of Iba-1-stained microglia in the ipsilateral spinal cord of PSNL mice, which were significantly suppressed by the administration of NAC/PPT. <b>Conclusions</b>: These results suggest that the post-onset intranasal administration of NAC/PPT ameliorates mechanical allodynia by suppressing microglia induction and that intranasal delivery with PEG-PCL-Tat might be a useful tool for the pharmacological management of neuropathic pain.https://www.mdpi.com/1999-4923/17/1/44intranasal administrationcell-penetrating peptide-modified carrier<i>N</i>-acetyl-L-cysteineneuropathic painmechanical allodyniapartial sciatic nerve ligation |
| spellingShingle | Hiroshi Nango Ai Takahashi Naoto Suzuki Takumi Kurano Saia Sakamoto Taiki Nagatomo Toyofumi Suzuki Takanori Kanazawa Yasuhiro Kosuge Hiroko Miyagishi Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice Pharmaceutics intranasal administration cell-penetrating peptide-modified carrier <i>N</i>-acetyl-L-cysteine neuropathic pain mechanical allodynia partial sciatic nerve ligation |
| title | Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice |
| title_full | Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice |
| title_fullStr | Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice |
| title_full_unstemmed | Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice |
| title_short | Therapeutic Efficacy of Intranasal <i>N</i>-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice |
| title_sort | therapeutic efficacy of intranasal i n i acetyl l cysteine with cell penetrating peptide modified polymer micelles on neuropathic pain in partial sciatic nerve ligation mice |
| topic | intranasal administration cell-penetrating peptide-modified carrier <i>N</i>-acetyl-L-cysteine neuropathic pain mechanical allodynia partial sciatic nerve ligation |
| url | https://www.mdpi.com/1999-4923/17/1/44 |
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