Botulinum Toxin Type A-A Modulator of Spinal Neuron-Glia Interactions under Neuropathic Pain Conditions

Abstract

Neuropathic pain represents a significant clinical problem because it is a chronic condition often refractory to available therapy. Therefore, there is still a strong need for new analgesics. Botulinum neurotoxin A (BoNT/A) is used to treat a variety of clinical diseases associated with pain. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This review addresses the effects of BoNT/A on the relationship between glia and neurons under neuropathic pain. The inhibitory action of BoNT/A on synaptic vesicle fusion that blocks the release of miscellaneous pain-related neurotransmitters is known. However, increasing evidence suggests that the analgesic effect of BoNT/A is mediated through neurons and glial cells, especially microglia. In vitro studies provide evidence that BoNT/A exerts its anti-inflammatory effect by diminishing NF-κB, p38 and ERK1/2 phosphorylation in microglia and directly interacts with Toll-like receptor 2 (TLR2). Furthermore, BoNT/A appears to have no more than a slight effect on astroglia. The full activation of TLR2 in astroglia appears to require the presence of functional TLR4 in microglia, emphasizing the significant interaction between those cell types. In this review, we discuss whether and how BoNT/A affects the spinal neuron-glia interaction and reduces the development of neuropathy.

Keywords: BoNT/A; Snap-23; TLR2; TLR4; astroglia; interleukins; microglia.

Figure 1

Suggested mechanism of botulinum toxin type A action under neuropathic pain conditions. (A) Intrathecal (i.th.) as well as intraplantar (i.pl.) injections of BoNT/A relief pain in animal models of neuropathy. Recent evidence suggests the possible retrograde transport and transcytosis of BoNT/A, which might be at least partially responsible for its analgesic effect. (B) Peripheral administration of BoNT/A reduced spinal microglial, but not astroglial, activation after sciatic nerve injury. (C,D) The data obtained from in vitro studies revealed that BoNT/A can directly influence microglial cells and it is achieved through the modulation of TLR2 receptor, SNARE proteins and intracellular pathways in microglial cells. BoNT/A diminishes LPS-induced phosphorylation of p38, ERK1/2, and NF-κB and reduces the release of pro-inflammatory factors, such as IL-1β, IL-18, IL-6, and anti-inflammatory IL-10 in microglia. No effects of BoNT/A on astroglia were observed. Mechanism of BoNT/A in glial cells is related to activation of TLRs, type 2 and 4. Complete activation of TLR2 in astroglia requires the presence of the microglial TLR4 receptor. Glial cross-talk may explain the lack of effect of BoNT/A on astroglia and it was suggested that the molecular target of BoNT/A is TLR2. See detailed description in the text Abbreviations: SNAP, synaptosomal-associated protein; TLR, Toll-like receptor; MyD, myeloid differentiation primary response gene; ERK1/2, extracellular-signal-regulated kinase 1/2; NF-κB, nuclear factor-κB; NOS2, inducible nitric oxide synthase; IL, interleukin; LPS, lipopolysaccharide, BoNT/A, botulinum toxin serotype A.