Minocycline-Loaded Poly(α-Lipoic Acid)–Methylprednisolone Prodrug Nanoparticles for the Combined Anti-Inflammatory Treatment of Spinal Cord Injury

Spinal cord injury (SCI) results in massive secondary damage characterized by a prolonged inflammation with phagocytic macrophage invasion and tissue destruction. In prior work, sustained subdural infusion of anti-inflammatory compounds reduced neurological deficits and reduced pro-inflammatory cell invasion at the site of injury leading to improved outcomes. We hypothesized that implantation of a hydrogel loaded with an immune modulating biologic drug, Serp-1, for sustained delivery after crush-induced SCI would have an effective anti-inflammatory and neuroprotective effect. Rats with dorsal column SCI crush injury, implanted with physical chitosan-collagen hydrogels (CCH) had severe granulomatous infiltration at the site of the dorsal column injury, which accumulated excess edema at 28 days post-surgery. More pronounced neuroprotective changes were observed with high dose (100 µg/50 µL) Serp-1 CCH implanted rats, but not with low dose (10 µg/50 µL) Serp-1 CCH. Rats treated with Serp-1 CCH implants also had improved motor function up to 20 days with recovery of neurological deficits attributed to inhibition of inflammation-associated tissue damage. In contrast, prolonged low dose Serp-1 infusion with chitosan did not improve recovery. Intralesional implantation of hydrogel for sustained delivery of the Serp-1 immune modulating biologic offers a neuroprotective treatment of acute SCI.

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Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota

Journal of Neuroinflammation ◽

10.1186/s12974-021-02123-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Emma K. A. Schmidt ◽

Pamela J. F. Raposo ◽

Abel Torres-Espin ◽

Keith K. Fenrich ◽

Karim Fouad

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Spinal Cord Injury ◽

Nervous System ◽

Gut Microbiota ◽

Microglial Activation ◽

Motor Recovery ◽

Long Term Effects ◽

Cord Injury ◽

Anti Inflammatory

Abstract Background Minocycline is a clinically available synthetic tetracycline derivative with anti-inflammatory and antibiotic properties. The majority of studies show that minocycline can reduce tissue damage and improve functional recovery following central nervous system injuries, mainly attributed to the drug’s direct anti-inflammatory, anti-oxidative, and neuroprotective properties. Surprisingly the consequences of minocycline’s antibiotic (i.e., antibacterial) effects on the gut microbiota and systemic immune response after spinal cord injury have largely been ignored despite their links to changes in mental health and immune suppression. Methods Here, we sought to determine minocycline’s effect on spinal cord injury-induced changes in the microbiota-immune axis using a cervical contusion injury in female Lewis rats. We investigated a group that received minocycline following spinal cord injury (immediately after injury for 7 days), an untreated spinal cord injury group, an untreated uninjured group, and an uninjured group that received minocycline. Plasma levels of cytokines/chemokines and fecal microbiota composition (using 16s rRNA sequencing) were monitored for 4 weeks following spinal cord injury as measures of the microbiota-immune axis. Additionally, motor recovery and anxiety-like behavior were assessed throughout the study, and microglial activation was analyzed immediately rostral to, caudal to, and at the lesion epicenter. Results We found that minocycline had a profound acute effect on the microbiota diversity and composition, which was paralleled by the subsequent normalization of spinal cord injury-induced suppression of cytokines/chemokines. Importantly, gut dysbiosis following spinal cord injury has been linked to the development of anxiety-like behavior, which was also decreased by minocycline. Furthermore, although minocycline attenuated spinal cord injury-induced microglial activation, it did not affect the lesion size or promote measurable motor recovery. Conclusion We show that minocycline’s microbiota effects precede its long-term effects on systemic cytokines and chemokines following spinal cord injury. These results provide an exciting new target of minocycline as a therapeutic for central nervous system diseases and injuries.

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An in vivo model of anti-inflammatory activity of subdural dexamethasone following the spinal cord injury

Neurologia i Neurochirurgia Polska ◽

10.1016/j.pjnns.2015.10.006 ◽

2016 ◽

Vol 50 (1) ◽

pp. 7-15 ◽

Cited By ~ 12

Author(s):

Jacek M. Kwiecien ◽

Bozena Jarosz ◽

Wendy Oakden ◽

Michal Klapec ◽

Greg J. Stanisz ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Activity ◽

In Vivo Model ◽

Cord Injury ◽

Anti Inflammatory

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Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention

Journal of Chemical Neuroanatomy ◽

10.1016/j.jchemneu.2017.08.001 ◽

2018 ◽

Vol 87 ◽

pp. 25-31 ◽

Cited By ~ 30

Author(s):

Emrullah Hayta ◽

Hasan Elden

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Acute Spinal Cord Injury ◽

Pharmacological Intervention ◽

Cord Injury ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Anti-inflammatory and antioxidant effects of astaxanthin following spinal cord injury in a rat animal model

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.10.014 ◽

2021 ◽

Author(s):

Alireza Masoudi ◽

Masoumeh Jorjani ◽

Morteza Alizadeh ◽

Solmaz mirzamohamadi ◽

Mola Mohammadi

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Animal Model ◽

Cord Injury ◽

Anti Inflammatory ◽

Antioxidant Effects ◽

Rat Animal Model

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Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-020-01973-4 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Hong Fan ◽

Hai-Bin Tang ◽

Zhe Chen ◽

Hu-Qing Wang ◽

Lei Zhang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Western Blot ◽

Functional Recovery ◽

Sterile Inflammation ◽

Qrt Pcr ◽

Cord Injury ◽

Microglia Polarization ◽

Anti Inflammatory ◽

Inflammatory Macrophages

Abstract Background Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. Methods In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. Results Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. Conclusions The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.

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