Anti-Inflammatory Treatments during the Chronic Phase of Spinal Cord Injury Improve Locomotor Function in Adult Mice

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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Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury: a systematic review

Journal of Neurosurgery Spine ◽

10.3171/2021.7.spine21537 ◽

2021 ◽

pp. 1-21

Author(s):

Charlotte Y. Adegeest ◽

Jort A. N. van Gent ◽

Janneke M. Stolwijk-Swüste ◽

Marcel W. M. Post ◽

William P. Vandertop ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Chronic Phase ◽

Autonomic Dysreflexia ◽

Traumatic Spinal Cord Injury ◽

Chronic Stage ◽

Increased Risk ◽

Cord Injury ◽

Meta Analyses

OBJECTIVE Secondary health conditions (SHCs) are long-term complications that frequently occur due to traumatic spinal cord injury (tSCI) and can negatively affect quality of life in this patient population. This study provides an overview of the associations between the severity and level of injury and the occurrence of SHCs in tSCI. METHODS A systematic search was conducted in PubMed and Embase that retrieved 44 studies on the influence of severity and/or level of injury on the occurrence of SHCs in the subacute and chronic phase of tSCI (from 3 months after trauma). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS In the majority of studies, patients with motor-complete tSCI (American Spinal Injury Association [ASIA] Impairment Scale [AIS] grade A or B) had a significantly increased occurrence of SHCs in comparison to patients with motor-incomplete tSCI (AIS grade C or D), such as respiratory and urogenital complications, musculoskeletal disorders, pressure ulcers, and autonomic dysreflexia. In contrast, an increased prevalence of pain was seen in patients with motor-incomplete injuries. In addition, higher rates of pulmonary infections, spasticity, and autonomic dysreflexia were observed in patients with tetraplegia. Patients with paraplegia more commonly suffered from hypertension, venous thromboembolism, and pain. CONCLUSIONS This review suggests that patients with a motor-complete tSCI have an increased risk of developing SHCs during the subacute and chronic stage of tSCI in comparison with patients with motor-incomplete tSCI. Future studies should examine whether systematic monitoring during rehabilitation and the subacute and chronic phase in patients with motor-complete tSCI could lead to early detection and potential prevention of SHCs in this population.

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Genetic Ablation of Transcription Repressor Bach1 Reduces Neural Tissue Damage and Improves Locomotor Function after Spinal Cord Injury in Mice

Journal of Neurotrauma ◽

10.1089/neu.2008.0667 ◽

2009 ◽

Vol 26 (1) ◽

pp. 31-39 ◽

Cited By ~ 33

Author(s):

Haruo Kanno ◽

Hiroshi Ozawa ◽

Yoshihiro Dohi ◽

Akira Sekiguchi ◽

Kazuhiko Igarashi ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Tissue Damage ◽

Neural Tissue ◽

Locomotor Function ◽

Genetic Ablation ◽

Cord Injury

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Intraspinal Injection of Platelet-Rich Plasma Promotes Regeneration of the Spinal Cord and Improves Locomotor Function by Modulating the Apoptosis and the Wnt Signaling Pathways

10.21203/rs.3.rs-365438/v1 ◽

2021 ◽

Author(s):

Zahra Behroozi ◽

Fatemeh Ramezani ◽

farinaz Nasirinezhad

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Wnt Signaling ◽

Motor Function ◽

Platelet Rich Plasma ◽

Wnt Signaling Pathway ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord ◽

Locomotor Function ◽

Cord Injury

Abstract Background: There are complex mechanisms for reducing intrinsic repair ability and neuronal regeneration following spinal cord injury (SCI). Platelet-rich plasma (PRP) is a rich source of growth factors and has been used to stimulate regeneration of peripheral nerves in degenerationtive diseases. However, only a few studies have investigated the effects of PRP on the SCI models. We examined whether PRP derived from human umbilical cord blood (HUCB-PRP) could recover motor function in animals with spinal cord injury. We also investigate the role of Wnt signaling pathway.Methods: Ault male Wistar rats were randomly divided into 6 groups (n=60) as control, sham, SCI, vehicle (SCI+platelet-poor plasma), PRP2day (SCI+injection 2 days after SCI) and PRP14day (SCI+injection 14 days after SCI). SCI was performed at the T12-T13 level. BBB tests were done weekly after injury for six weeks. caspase3 expression was determined using the Immunohistochemistry technique. The expression of GSK3β, Tau and MAG were determined using the Western blot technique. Data were analyzed by PRISM & SPSS software. Results: PRP injected animals showed a higher locomotor function recovery than those in the SCI group (p<0.0001). The level of caspase3, GSK3β and CSF- Tau reduced and MAG level in the spinal cord increased by injection of HUCB-PRP in animals with spinal cord injury. Conclusions: Injection of HUCB-PRP enhanced hind limb locomotor performance by modulation of caspase3, GSK3β, tau and MAG expression. Using HUCB-PRP could be a new therapeutic option for recovering the motor function and axonal regeneration after spinal cord injury.

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Inhibition of x-irradiation–enhanced locomotor recovery after spinal cord injury by hyperbaric oxygen or the antioxidant nitroxide tempol

Journal of Neurosurgery Spine ◽

10.3171/spi.2007.6.4.9 ◽

2007 ◽

Vol 6 (4) ◽

pp. 337-343 ◽

Cited By ~ 7

Author(s):

Virany H. Hillard ◽

Hong Peng ◽

Kaushik Das ◽

Raj Murali ◽

Chitti R. Moorthy ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Hyperbaric Oxygen ◽

Spinal Cord Tissue ◽

Irradiation Site ◽

Injury Site ◽

Locomotor Recovery ◽

Locomotor Function ◽

Cord Injury ◽

X Irradiation

Object Hyperbaric oxygen (HBO), the nitroxide antioxidant tempol, and x-irradiation have been used to promote locomotor recovery in experimental models of spinal cord injury. The authors used x-irradiation of the injury site together with either HBO or tempol to determine whether combined therapy offers greater benefit to rats. Methods Contusion injury was produced with a weight-drop device in rats at the T-10 level, and recovery was determined using the 21-point Basso-Beattie-Bresnahan (BBB) locomotor scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater after x-irradiation (20 Gy) of the injury site or treatment with tempol (275 mg/kg intraperitoneally) than in untreated rats (final BBB Scores 10.6 [x-irradiation treated] and 9.1 [tempol treated] compared with 6.4 [untreated], p < 0.05). Recovery was not significantly improved by HBO (2 atm for 1 hour [BBB Score 8.2, p > 0.05]). Interestingly, the improved recovery of locomotor function after x-irradiation, in contrast with antiproliferative radiotherapy for neoplasia, was inhibited when used together with either HBO or tempol (BBB Scores 8.2 and 8.3, respectively). The ability of tempol to block enhanced locomotor recovery by x-irradiation was accompanied by prevention of alopecia at the irradiation site. The extent of locomotor recovery following treatment with tempol, HBO, and x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. Conclusions These results suggest that these treatments, when used alone, can activate neuroprotective mechanisms but, in combination, may result in neurotoxicity.

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