Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

Abstract

Demyelination in multiple sclerosis (MS) leads to significant, progressive axonal and neuronal degeneration. Currently existing immunosuppressive and immunomodulatory therapies alleviate MS symptoms and slow, but fail to prevent or reverse, disease progression. Restoration of damaged myelin sheath by replenishment of mature oligodendrocytes (OLs) should not only restore saltatory axon conduction, but also provide a major boost to axon survival. Our previous work has shown that therapeutic treatment with the modestly selective generic estrogen receptor (ER) β agonist diarylpropionitrile (DPN) confers functional neuroprotection in a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS by stimulating endogenous myelination. Recently, we found that the more potent, selective ERβ agonist indazole-chloride (Ind-Cl) improves clinical disease and motor performance. Importantly, electrophysiological measures revealed improved corpus callosal conduction and reduced axon refractoriness. This Ind-Cl treatment-induced functional remyelination was attributable to increased OL progenitor cell (OPC) and mature OL numbers. At the intracellular signaling level, transition of early to late OPCs requires Erk1/2 signaling, and transition of immature to mature OLs requires mTOR signaling; thus, the PI3K/Akt/mTOR pathway plays a major role in the late stages of OL differentiation and myelination. Indeed, therapeutic treatment of EAE mice with various ERβ agonists results in increased brain-derived neurotrophic factor (BDNF) and phosphorylated (p) Akt and p-mTOR levels. It is notable that while DPN’s neuroprotective effects occur in the presence of peripheral and central inflammation, Ind-Cl is directly neuroprotective, as demonstrated by remyelination effects in the cuprizone-induced demyelination model, as well as anti-inflammatory. Elucidating the mechanisms by which ER agonists and other directly remyelinating agents modulate endogenous OPC and OL regulatory signaling is critical to the development of effective remyelinating drugs. The discovery of signaling targets to induce functional remyelination will valuably contribute to the treatment of demyelinating neurological diseases, including MS, stroke, and traumatic brain and spinal cord injury.

Recurrent Stroke-Like Symptoms After Cesarean Section Deliveries in a Female Patient With X-Linked Charcot-Marie-Tooth Type 1

“…However, how does the puerperium after cesarean delivery trigger CNS symptoms in the female patient with CMTX1? We speculated that hormonal changes that physiologically occur in puerperium (abrupt drop in estrogen and progesterone levels) would hamper the proliferation and maturation of oligodendrocyte progenitor cells to mature oligodendrocytes (18)(19)(20). Thus, the female patient with CMTX1 who had fragile oligodendrocyte gap junction coupling due to Cx32 mutation may be more vulnerable in puerperium, leading to recurrent stroke-like symptoms.…”

A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination

“…Signals that block activation of AKT have also been implicated in regulating developmental myelination and remyelination (reviewed by Gaesser & Fyffe‐Maricich, ), while the Leucine rich repeat and Immunoglobulin‐like domain‐containing Nogo receptor interacting protein 1 (LINGO‐1) acts as a negative regulator of OPC differentiation through a mechanism that includes downregulation of gelsolin, an abundant actin‐severing protein involved in the depolymerization of actin filaments (Mi et al, ; Mi, Pepinsky, & Cadavid, ; Shao et al, ). In contrast, estrogen receptor‐β agonists have been implicated in promoting functional remyelination (reviewed by Khalaj, Hasselmann, Augello, Moore, & Tiwari‐Woodruff, ). Interestingly, HA and its receptor, CD44, can influence each of these pathways.…”

Matrine protects retinal ganglion cells from apoptosis in experimental optic neuritis

“…until the end of the experiment (day 19 after p.i. ); (2) immunized rats that received vehicle via i.p. served as control; (3) non-immunized naïve rats that received vehicle i.p.…”