Polyamidoamine dendrimer-conjugated triamcinolone acetonide attenuates nerve injury-induced spinal cord microglia activation and mechanical allodynia.
Background Accumulating evidence on the causal role of spinal cord microglia activation in the development of neuropathic pain after peripheral nerve injury suggests that microglial activation inhibitors might be useful analgesics for neuropathic pain. Studies also have shown that polyamidoamine dendrimer may function as a drug delivery vehicle to microglia in the central nervous system. In this regard, we developed polyamidoamine dendrimer-conjugated triamcinolone acetonide, a previously identified microglial activation inhibitor, and tested its analgesic efficacy in a mouse peripheral nerve injury model. Result Polyamidoamine dendrimer was delivered selectively to spinal cord microglia upon intrathecal administration. Dendrimer-conjugated triamcinolone acetonide inhibited lipoteichoic acid-induced proinflammatory gene expression in primary glial cells. In addition, dendrimer-conjugated triamcinolone acetonide administration (intrathecal) inhibited peripheral nerve injury-induced spinal cord microglial activation and the expression of pain-related genes in the spinal cord, including Nox2, IL-1β, TNF-α, and IL-6. Dendrimer-conjugated triamcinolone acetonide administration right after nerve injury almost completely reversed peripheral nerve injury-induced mechanical allodynia for up to three days. Meanwhile, dendrimer-conjugated triamcinolone acetonide administration 1.5 days post injury significantly attenuated mechanical allodynia. Conclusion Our data demonstrate that dendrimer-conjugated triamcinolone acetonide inhibits spinal cord microglia activation and attenuates neuropathic pain after peripheral nerve injury, which has therapeutic implications for the treatment of neuropathic pain.
1 Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Hwisung
H
Kim
1 Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Boomin
B
Choi
1 Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Hyoungsub
H
Lim
1 Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Hyunjung
H
Min
2 School of Chemistry and Molecular Engineering, Seoul National University, Seoul, Republic of Korea.
Jae Hoon
JH
Oh
2 School of Chemistry and Molecular Engineering, Seoul National University, Seoul, Republic of Korea.
Sunghyun
S
Choi
3 Department of Anesthesiology and Pain Medicine, National Health Insurance Service Ilsan Hospital, Ilsan, Republic of Korea.
Joung Goo
JG
Cho
2 School of Chemistry and Molecular Engineering, Seoul National University, Seoul, Republic of Korea.
Jong-Sang
JS
Park
1 Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Sung Joong
SJ
Lee
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000150:complications* / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology*; D014222:Triamcinolone Acetonide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C491049:Aif1 protein, mouse; D000893:Anti-Inflammatory Agents; D002135:Calcium-Binding Proteins; D016207:Cytokines; D050091:Dendrimers; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D014222:Triamcinolone Acetonide
Dendrimer-triamcinolone acetonide; neuropathic pain; peripheral nerve injury; spinal cord microglia