Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis

Abstract

Myelin-associated inhibitors, such as NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp), play a pivotal role in the lack of neuroregeneration in multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). Matrine (MAT), a monomer that is used in traditional Chinese medicine as an anti-inflammatory agent, has shown beneficial effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the underlying mechanisms of MAT-induced EAE amelioration are not fully understood. In the present study, we show that MAT treatment suppressed ongoing EAE, and this effect correlated with an increased expression of growth-associated protein 43, an established marker for axonal regeneration. MAT treatment significantly reduced the levels of NogoA, its receptor complex NgR/p75NTR/LINGO-1, and their downstream RhoA/ROCK signaling pathway in the CNS. In contrast, intracellular cyclic AMP (cAMP) levels and its protein kinase (protein kinase A (PKA)), which can promote axonal regrowth by inactivating the RhoA, were upregulated. Importantly, adding MAT in primary astrocytes in vitro largely induced cAMP/PKA expression, and blockade of cAMP significantly diminished MAT-induced expression of PKA and production of BDNF, a potent neurotrophic factor for neuroregeneration. Taken together, our findings demonstrate that the beneficial effects of MAT on EAE can be attributed not only to its capacity for immunomodulation, but also to its directly promoting regeneration of the injured CNS.

Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway

“…Matrine, which was approved by Chinese FDA (CFDA) in 1995, is derived primarily from Sophora species plants and has a chemical formula of C 15 H 24 N 2 O (5). Matrine exhibits a wide range of pharmacological effects and has long been applied to treat viral hepatitis (6), neuropathic pain (7), isoproterenol-induced cardiotoxicity inflammatory and other diseases (8,9). In addition, increasing evidence has revealed that matrine displays anticancer effects in various cancers, such as gastric (10), rhabdomyosarcoma (11), acute myeloid leukemia (12), osteosarcoma (13), prostate (14), breast (15) and lung cancer (16).…”

Matrine protects retinal ganglion cells from apoptosis in experimental optic neuritis

“…In summary, our study demonstrates that MAT effectively suppresses CNS in ammation, demyelination and axonal loss in optic nerves, as well as RGC apoptosis in experimental ON. The mechanisms underlying these effects may include: 1) its anti-in ammatory effects (18,19,38); 2) the potential to promote production of neurotrophic factors, such as NGF and BDNF, as previously reported (14,15). These effects, together, could convert a hostile environment into a supportive one for neural cells, thus reducing myelin and axonal damage of the optic nerve and protecting RGCs from apoptosis.…”

“…Matrine (MAT), a natural quinolizidine alkaloid compound extracted from the herb root of Sophorae avescens, with a molecular weight (MW) of 258.43 (C 15 H 24 N 2 O) (14)(15)(16), is known for its various effects in animal models of EAE, including protection against apoptosis, tumor and brotic tissue development, and in ammation (17). We have recently shown that MAT can ameliorate clinical signs and alleviate neuro-axonal injury in the CNS of EAE animals by regulatory T cells, reducing Th1 and Th17 cells in the CNS and periphery and increasing the number of neural protective molecules (18,19).…”

Immunomodulatory and neuroprotective mechanisms of Huangqi glycoprotein treatment in experimental autoimmune encephalomyelitis

“…Natural compounds and their derivatives have become an important source of new MS therapies [7,14,20]. The dry root of Astragalus membranaceus (commonly known as Huang Qi) is one of the most commonly used Chinese traditional medicines for its multitude of beneficial effects that include liver protection, anti-aging, anti-stress, and has been used to treat immune-related diseases [13,15,31].…”