Blood–spinal cord barrier breakdown and pericyte deficiency in peripheral neuropathy

Abstract

The blood-spinal cord barrier (BSCB) prevents leakage of molecules, such as pronociceptive mediators, into the spinal cord, but its role in the pathophysiology of neuropathic pain is not completely understood. Rats with chronic constriction injury (CCI) develop mechanical allodynia, thermal hypersensitivity, and reduced motor performance (Rota-Rod test) compared with sham-injured mice-similar to mice with spared nerve injury (SNI). The BSCB becomes permeable for small and large tracers 1 day after nerve ligation. Messenger RNA (mRNA) expression of tight junction proteins (TJPs) occludin, claudin-1, claudin-5, claudin-19, tricellulin, and ZO-1 significantly declines 7-14 days after CCI or SNI. ZO-1 and occludin are reduced in the cell membrane. In capillaries isolated from the spinal cord, immunoreactivity of claudin-5 and ZO-1 is fainter. In parallel, the number of platelet-derived growth factor receptor β (PDGF-β) and CD13 pericytes in the spinal cord drops. Reduced levels of cytosolic transcription factors like β-catenin, but not SMAD4 and SLUG, could account for reduced TJP mRNA. In summary, neuropathy-induced allodynia/hypersensitivity is accompanied by a loss of pericytes in the spinal cord and a leaky BSCB. A better understanding of these pathways and mechanisms in neuropathic pain might foster the design of novel treatments to maintain spinal cord homeostasis.

Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painfulness in polyneuropathy

“…Deletion of Cldn12 gene via KO or siRNA in the SN led to mechanical allodynia. Although nerve injury drives loss of tight junction protein expression and barrier opening in the PNS and spinal cord (4,5,13,51), it is unknown whether this is sufficient to cause pain. Indeed, barrier opening by tissue plasminogen activator (4), by siRNA or peptides against Cldn1 opens the perineurial barrier without causing hypersensitivity (6,11).…”

“…Filaments were applied in ascending order from 0.008 g to 1.4 g. In general, the filaments were applied to the plantar surface of the ipsilateral and contralateral hind paw and were held for 1-3 s until the filaments were bent to an angle of 45°. We determined the withdrawal threshold of the hind-limbs to a mechanical stimulus by using 50% paw withdrawal threshold (PWT) method (4,51).…”

“…Thermal nociceptive behavior responses were assessed by the Hargreaves method (Chen et al, 2014;Sauer et al, 2017;Reinhold et al, 2019). Static mechanical hypersensitivity was measured using von Frey filaments (Ugo Basile SRL, Italy) by using 50% paw withdrawal threshold (PWT) method (Chen et al, 2014;Sauer et al, 2017;Reinhold et al, 2019).…”

Effect of mirabegron on tight junction molecules in primary cultured rat Sertoli cells

“…The sequences of oligonucleotide primer pairs for claudin‐11, occludin, ZO‐1 and beta‐actin mRNA in rats were obtained from previous reports (Chung, Mruk, Mo, Lee, & Cheng, ; Lui, Lee, & Cheng, ; Sauer et al, ; Shi et al, ) and purchased from Europhinsgenomics. The sequences are shown in Table .…”

Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats

“…While many of these characteristics are similar in the blood-nerve barrier and blood-brain barrier, distinct features, such as absence of several neurotransmitter transporters and lack of astrocytes in the periphery, qualify the blood-nerve barrier as a specialized, unique structure [9].After axonal injury or acute demyelination, extravasation of blood-borne molecules such as albumin and intraneural edema as correlates of blood-nerve barrier leakage can be observed [10]. Studies of the blood-nerve barrier in nerve injury models have revealed downregulation of Cldn1, Cldn5, Ocln, Tjp1 (ZO-1) and Jam3 (JAMC) mRNA in the sciatic nerve [10][11][12][13][14] as well as Tjp1 (ZO-1), Cldn5 and Ocln in the spinal cord of rats [15,16]. Similar studies observed reductions of Cldn1 and Tjp1 (ZO-1) mRNA and immunoreactivity (IR) in the sciatic nerves of mice [13].…”