Myristoylated alanine‐rich C‐kinase substrate effector domain peptide improves sex‐specific recovery and axonal regrowth after spinal cord injury

Abstract

Myristoylated alanine‐rich C‐kinase substrate (MARCKS) is an intracellular receptor for polysialic acid. MARCKS supports development, synaptic plasticity, and regeneration after injury. MARCKS binds with its functionally essential effector domain (ED) to polysialic acid. A 25‐mer peptide comprising the ED of MARCKS stimulates neuritogenesis of primary hippocampal neurons after addition to the culture. This motivated us to investigate whether ED peptide has similar effects in spinal cord injury. ED peptide supported recovery and regrowth of monoaminergic axons in female, but not in male mice. Sex‐specific differences in response to ED peptide application also occurred in cultured neurons. In female but not male neurons, the ED peptide enhanced neurite outgrowth that could be suppressed by inhibitors of the estrogen receptors α and β, fibroblast growth factor receptor‐1, protein kinase C, and matrix metalloproteinase 2. In addition, we observed female‐specific elevation of phosphorylated MARCKS levels after ED peptide treatment. In male neurons, the ED peptide enhanced neuritogenesis in the presence of an androgen receptor inhibitor to the extent seen in ED peptide‐treated female neurons. However, inhibition of androgen receptor did not lead to increased phosphorylation of MARCKS. These results provide insights into the functions of a novel compound contributing to gender‐dependent regeneration.

Electro‐acupuncture and its combination with adult stem cell transplantation for spinal cord injury treatment: A summary of current laboratory findings and a review of literature

“…More clinical studies are clearly desirable to ensure the safety profile of such treatment and to support the translation of this treatment model into a wide range of clinical settings. In addition, some researches indicated that sex differences exist a certain effect on the repair of central nervous system injury 108‐114 . Hence, future study should pay attention to the potential influence of sex differences on electro‐acupuncture and its combination with adult stem cell transplantation for spinal cord injury treatment.…”

“…In addition, some researches indicated that sex differences exist a certain effect on the repair of central nervous system injury. 108 , 109 , 110 , 111 , 112 , 113 , 114 Hence, future study should pay attention to the potential influence of sex differences on electro‐acupuncture and its combination with adult stem cell transplantation for spinal cord injury treatment.…”

CHL1-Deficient and Wild-Type Male Mice do Not Differ in Locomotor Recovery from Spinal Cord Injury

“…Mouse spinal cords were severely contused at T11 as described [ 16 ]. In brief, mice were anesthetized with isoflurane, initially at 5%.…”

“…A laminectomy at T9-10 vertebral level exposed the spinal cord and the adjacent spinous processes were secured with clamps. The spinal cord was contused at T11 with a 5-g weight-drop from a 6.25 mm height using the Multicenter Animal Spinal Cord Injury Study Impactor device [ 16 ]. After contusion, paravertebral muscles adjacent to the laminectomy site were sutured and the skin was closed with 9 mm wound clips (cat# RS-9260; Roboz Surgical Instrument Co, Maryland, USA).…”

Investigating Mimetics of a Peptide Derived from the Effector Domain of MARCKS as Possible Therapeutics for Spinal Cord Injury

“…The ED peptide triggers neurite outgrowth of neurons, increases functional recovery, and enhances phosphorylation levels of MARCKS in neurons and spinal cords in female mice but not male mice. [24] Although the ED peptide shows promising effects on SCI models, it cannot be administered intravenously because the blood-brain barrier protects the central nervous system from some peptides. To allow for an intravenous treatment option for SCI using the MARCKS-PSA pathway, we are looking for ED peptide mimetics-compounds that mimic the structure and function of the ED peptide-that also cross the blood-brain barrier.…”