Inhibit inflammation and apoptosis of pyrroloquinoline on spinal cord injury in rat

Abstract

Background: Pyrroloquinoline quinone (PQQ) is a redox cofactor that can participate in a variety of physiological and biochemical processes, such as anti-inflammatory, cytoprotection, anti-aging, and antiapoptosis. PQQ plays an important protective role in the central nervous system (CNS). However, the effects of PQQ on astrocytes of the CNS and spinal cord injury (SCI) of rats is still unclear. The present study investigates the role of PQQ in inflammation, apoptosis, and autophagy after SCI in rats. And the effect of PQQ on lipopolysaccharide (LPS)-induced apoptosis and inflammation of astrocytes in vitro, to explore the neuroprotective mechanism of PQQ.Methods: 60 specific pathogen free (SPF) SD male rats (200-250 g) were randomly divided into Normal group, Sham group, SCI group, and SCI + PQQ group, with 15 rats in each group. BBB score, HE staining, Nissl staining, Western blot, immunofluorescence, and other methods were used for detection.Results: Our results showed that PQQ could upregulate BBB score in SCI rats. In the second place, PQQ can increase the number and improve the morphology of neurons after SCI. The expression of IL-1β, TNF-α, IL-6 was significantly decreased after PQQ treatment. And then, the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax) increased significantly, and the positive signal of NeuN increased obviously after PQQ treatment. There are a large number of co-localizations between Bcl-2 and NeuN.Meanwhile, PQQ could down-regulate the expression of Active-Caspase3, and PQQ treatment could reverse the transfer of Active-Caspase3/Caspase3 from the cytoplasm to the nucleus in neurons and astrocytes after SCI. At the same time, PQQ had no significant effect on the LC3b/a ratio. PQQ could decrease the LAMP2 expression in spinal cord after injury. The expression level of phospho-Akt (p-AKT) increased after SCI and decreased after PQQ treatment. In primary astrocytes, LPS could induce the expression levels of IL-1β, TNF-α, and IL-6, and which were inhibited by PQQ treatment at 12 hours. After treatment with LPS, the expression level of Active-Caspase3 increased, which could be reversed by PQQ treatment for 24 h.Conclusions: These results suggest that PQQ can ameliorate the motor function of hind limbs and the pathological changes of neurons and injured spinal cord after SCI, down-regulate the expressions of IL-1β, TNF-α, and IL-6, inhibit apoptosis after SCI, and inhibit LPS-induced apoptosis and inflammation of astrocytes.

Biological role of mitochondrial TLR4‐mediated NF‐κB signaling pathway in central nervous system injury

“…72,84,98 Then NF-κB translocates to the nucleus, rapidly regulating the transcription of inflammatory mediators such as TNF-α, IL-1β, iNOS2, COX-2 while also mediating the downregulation of antiapoptotic genes such as BCL-2, BCL-xL, and the upregulation of proapoptotic genes such as Bax and Bak. [23][24][25][26] During the process of LPS-induced neuronal cell apoptosis, the positive feedback regulation between ANT1 and NF-κB accelerates the process of cell apoptosis by continuously increasing ANT1 expression and decreasing the expression of antiapoptotic genes by reducing NF-κB translocation to the nucleus. In contrast, STAT3, which is phosphorylated before acetylation, can bind to phosphorylated RelA, inducing changes in the NF-κB gene transcription pattern in the nucleus, resulting in the downregulation of proapoptotic gene expression and the upregulation of antiapoptotic gene expression, thereby protecting neurons.…”

“…In experimental research, LPS is frequently employed to instigate CNS inflammation, robustly activating the TLR4/NF‐κB signaling pathway in neuronal cells 72,84,98 . Then NF‐κB translocates to the nucleus, rapidly regulating the transcription of inflammatory mediators such as TNF‐α, IL‐1β, iNOS2, COX‐2 while also mediating the downregulation of antiapoptotic genes such as BCL‐2, BCL‐xL, and the upregulation of proapoptotic genes such as Bax and Bak 23–26 . During the process of LPS‐induced neuronal cell apoptosis, the positive feedback regulation between ANT1 and NF‐κB accelerates the process of cell apoptosis by continuously increasing ANT1 expression and decreasing the expression of antiapoptotic genes by reducing NF‐κB translocation to the nucleus.…”

“…Upon nuclear translocation, NF‐κB rapidly regulates the transcription of inflammatory mediators such as TNF‐α, IL‐1β, inducible nitric oxide synthase 2 (iNOS2), and cyclooxygenase‐2 (COX‐2) 23 . On the other hand, it downregulates the expression of antiapoptotic genes such as BCL‐2 and BCL‐xL while upregulating the expression of proapoptotic genes such as Bax and Bak, 24–26 ultimately stimulating the production of mitochondrial ROS such as free radicals, peroxides, and ions. The sustained production of ROS can disrupt the balance of the mitochondrial membrane potential and activate caspases to induce IL‐1β maturation, which further exacerbates the inflammatory response and induces cell apoptosis 27–29 …”

Nacre-inspired magnetically oriented micro-cellulose fibres/nano-hydroxyapatite/chitosan layered scaffold enhances pro-osteogenesis and angiogenesis

“…Furthermore, while considering mechanical strength, we also developed a plan for an acute inflammatory response. Pyrroloquinoline quinone (PQQ) is a natural antioxidant [ 38 ] with antiaging properties [ 39 ]. Recently, PQQ was reported to regulate multiple intracellular signalling pathways, including the RANKL-mediated c-Fos/NFATc1 pathway [ 40 ]; activation of the Ras pathway [ 41 ], and CREB-dependent mitochondrial production [ 42 ].…”

“…Recently, PQQ was reported to regulate multiple intracellular signalling pathways, including the RANKL-mediated c-Fos/NFATc1 pathway [ 40 ]; activation of the Ras pathway [ 41 ], and CREB-dependent mitochondrial production [ 42 ]. The reported anti-inflammatory effects of PQQ mostly focused on the treatment of microglia [ 43 ], acute liver injury [ 44 ] and acute spinal cord injury [ 39 ], and studies have found that PQQ plays a role in inhibiting the NF-κB signalling pathway [ 40 ]. The NF-κB signalling pathway plays a key role in the acute inflammatory response.…”