Targeted intraspinal injections to assess therapies in rodent models of neurological disorders

Chen, Kevin S.; McGinley, Lisa M.; Kashlan, Osama N.; Hayes, John M.; Bruno, Elizabeth; Chang, Josh S.; Mendelson, Faye E.; Tabbey, Maegan A.; Johe, Karl; Sakowski, Stacey A.; Feldman, Eva L.

doi:10.1038/s41596-018-0095-5

Cited by 11 publications

(6 citation statements)

References 57 publications

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“…NSI-566RSC is an NPC cell line originally derived from the spinal cord of a human fetus in accordance with guidelines from the FDA, National Institute of Health (NIH), and an independent ethics review board, which can be differentiated into functional motor neurons [49]. Indeed, its engraftment into SOD1 G93A rat spinal cord delayed disease onset and progression, improved survival, and generated differentiated neurons that formed synapses with host neurons [50,51,52]. The NSI-566RSC cell line can be readily propagated and is therefore an accessible stem cell source; however, recipients must also receive immunosuppressants to prevent graft rejection.…”

Section: Stem Cell Sources In Human Als Clinical Trialsmentioning

confidence: 99%

Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials

Goutman

Savelieff

Sakowski

et al. 2019

Expert Opinion on Investigational Drugs

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Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of cortical, brainstem, and spinal motor neurons; it causes progressive muscle weakness and atrophy, respiratory failure and death. No currently available treatment either stops or reverses this disease. Therapeutics to slow, stop and reverse ALS are needed. Stem cells may be a viable solution to sustain and nurture diseased motor neurons. Several early stage clinical trials have been launched to assess the potential of stem cells for ALS treatment.Areas covered: This review covers the key advances from early phase clinical trials of stem cell therapy for ALS and identifies promising avenues and key challenges.Expert opinion: Clinical trials in humans are still in the nascent stages of development. It will be critical to ensure that powered, well-controlled trials are conducted, that optimal treatment windows are identified, and that the ideal cell type, cell dose, and delivery site and method are determined. Several trials have used more invasive procedures, and ethical concerns of sham procedures on patients in the control arm and on their safety should to be considered.

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Section: Stem Cell Sources In Human Als Clinical Trialsmentioning

confidence: 99%

Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials

Goutman

Savelieff

Sakowski

et al. 2019

Expert Opinion on Investigational Drugs

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“…The procedure for intraspinal (i.s.) injection in rats was adapted from established protocols [ 16 ]. Briefly, rats underwent deep anesthesia using isoflurane.…”

Section: Methodsmentioning

confidence: 99%

IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve

Yu,

Cui,

Jin

et al. 2024

J Neuroinflammation

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Background The spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure. Methods A chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION’s CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain. Results CCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION’s CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION’s CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION. Conclusion IL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions. Graphical abstract

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“…Then, the skin was incised to separate the subcutaneous connective tissue and muscle and fully expose the T12-L1 vertebral plate. A small amount of the lamina was removed at the junction of the lower edge of the T13 and the upper edge of the L1 vertebral body with occlusal forceps, working carefully and gently to avoid injury to the spinal cord ( Chen et al, 2019 ). Using a stereotaxic instrument and a microinjection device, siRNA was injected into the dorsal horn of the lumbar expanded segment of the spinal cord of rats using a glass pipette needle at .8 mm on the left side of the midline of the spinal cord with an insertion depth of .6 mm.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Huang

Ding

et al. 2023

Front. Pharmacol.

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Regulation of gene transcription in the spinal dorsal horn (SDH) plays a critical role in the pathophysiology of neuropathic pain. In this study, we investigated whether the transcription factor STAT2 affects neuropathic pain and evaluated its possible mechanisms. A proteomic analysis showed that the nuclear fraction of STAT2 protein in the SDH was downregulated after chronic constriction injury of the rat sciatic nerve, which was associated with the development of neuropathic pain. Similarly, siRNA-induced downregulation of STAT2 in the SDH of naïve rats also resulted in pain hypersensitivity. Using RNA-sequencing analysis, we showed that reduction of nuclear STAT2 after chronic constriction injury was associated with increased expression of microglial activation markers, including the class II transactivator and major histocompatibility complex class II proteins. In addition, siRNA-induced downregulation of STAT2 promoted microglial activation and pro-inflammatory cytokine expression in the SDH. Taken together, these results showed that chronic constriction injury caused downregulation of nuclear STAT2 in the SDH, which may result in microglial activation and development of neuropathic pain. Our findings indicate that restoration of nuclear expression of STAT2 could be a potential pathway for the treatment of neuropathic pain.

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Targeted intraspinal injections to assess therapies in rodent models of neurological disorders

Cited by 11 publications

References 57 publications

Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials

Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials

IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

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