In the present study, experimental SAH induced evident mortality and cognitive deficit in rats. EA treatment preserved cognitive function, and promoted remyelination in white matter in the late phase of SAH. Differentiation of OPCs and maturation of oligodendrocytes were promoted by EA. Moreover, the expression of Id2 was downregulated and SOX10 was downregulated by EA in the oligodendrocyte cells after SAH. The results showed that the attenuation of cognitive deficit by EA treatment after SAH may rely on the promoted remyelination in white matter. The mechanisms involve the modulation on the differentiation of OPCs and the regulation of transcription factor expression by EA treatment. Moreover, the improvement of CBF was observed in EA treatment rats, which may contribute to the protective effects of EA on the myelin.
Previous studies usually focus on the protection of gray matter and neurons in SAH, whereas white matter injury was usually overlooked. Recent studies have revealed that SAH induces white matter injury which includes the injury of axons and myelin sheath [4, 5]. In our previous work, white matter injury and demyelination were also observed in the early phase of SAH . However, the acute damage of myelin in SAH is difficult for prevention and treatment. Moreover, our previous clinical study observed the correlation between white matter injury and cognitive deficit in the long-term follow up after SAH . Remyelination is inhibited in the late phase of SAH. In the present work, we observed that the motor function of rats has recovered to the level of sham-operated ones on day 7 after SAH, while the cognitive deficit was observed throughout the late stage of SAH. Therefore, more attention needs to be paid in the recovery of neurological function and the remyelination in the late stage of SAH.
Recent work has revealed that oligodendrocytes and myelin play crucial roles in learning and memory . Speed of pulse conduction in myelinated axons which is associated with cognitive function is closely related to intact structure of myelin. The thickness of myelin sheath relative to the diameter of the wrapped axon (g-ratio) and internode length and spacing are main factors of myelin plasticity. An additional, crucial function of myelin-forming oligodendrocytes provide metabolic support to the ensheathed axons . In physiological conditions, decreased fractional anisotropy (FA) in white matter correlates with poor learning ability . Under pathological conditions, demyelination is strongly correlated to cognitive deficit. Multiple sclerosis is a typical demyelinating neurological disease, in which significant decline in cognitive function is related to demyelination . Myelin degeneration and diminished myelin renewal contribute to age-related impairment of memory . Imaging study also provides evidence of demyelination in cognitive impairment and dementia patient, which is characterized as decrease of myelin content . On the contrary, remyelination benefits cognitive recovery in neurological diseases. Chen et al. proved that enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease . Transplantation of OPCs is found to promotes remyelination and rescue cognitive function in radiation induced cognitive deficit . Therefore, promoting remyelination is a potential method for the recovery of intact neuronal function for the treatment of cognitive deficit in SAH.
Electroacupuncture is a traditional Chinese medical therapy which has been used in treating various of neurological diseases. The underlying mechanisms of EA’s curative effects are complicated. In recent study, EA is found to adjust body function through stimulating peripheral sensory nerve receptor distributing in specific areas . Our previous work showed that EA exerts protective effects on myelin sheath via promotion of oligodendrocyte proliferation and inhibition of oligodendrocyte death in a rat model of spinal cord injury . In the present study, the acupoints of Baihui (GV20) and Dazhui (GV14) were selected and were found to exert protective effect on myelin. It is previously reported that EA stimulation on Baihui (GV20) and Dazhui (GV14) enhances neurological recovery and reduces hemorrhage volume via anti-apoptosis in a model of intracerebral hemorrhage . Specifically, EA is observed to exert particular therapeutic effect on cognitive deficit. Wang et al. reported that EA improves learning and memory functions in a rat model of ischemia and reperfusion cerebral injury through activation of PI3K/Akt signaling pathway . Other mechanisms relating to the protective effect of EA on cognitive function involve improvement of impaired long-term potentiation (LTP) , restoration of hippocampal synaptic plasticity , and inhibition of neuroinflammation . In the present study, promotion of remyelination by EA was firstly observed in SAH and may provide new evidence for the treatment of cognitive deficit.
The recovery of integrity of neuronal functions relies on the remyelination of axons in SAH. Remyelination is based on two major processes which are the differentiation of OPCs and the subsequent maturation of oligodendrocytes [31, 32, 33]. In the present study, we observed that EA enhanced the differentiation of OPCs as well as increased the number of mature oligodendrocytes in white matter after SAH, which indicates that EA promotes the both processes of remyelination. Previous studies have showed that EA promotes proliferation [12, 34] and differentiation  of OPCs in a rat model of spinal cord injury. Huang et al. found that EA treatment promotes remyelination in the demyelinated spinal cord and improves the neurological outcome . These studies indicate that EA treatment is a promising method for the enhancement of remyelination. Specifically, promotion of remyelination by EA improves cognitive outcome. It is reported that EA promotes memory recovery following white matter injury through promoting oligodendrocyte regeneration via the NT4/5-TrkB signaling pathway . Our previous work found that EA exerts protective effects on myelin via modulating the interaction between Olig2 and Id2 . The modulatory effect of EA on remyelination was widely proved in neurological diseases. However, the detailed molecular mechanisms are still need investigating.
Transcriptional control of myelination and remyelination in physiological and pathological conditions is regulated by a complex network of transcriptional factors . Wherein Olig2 and Id2 are key factors in remyelination process. Olig2 plays positive roles in pattern formation and generation of OPCs and motor neurons , and Olig2-positive OPCs are deemed as specific precursor cells for oligodendrocyte development. On the other hand, Id2 is a member of the inhibitor of differentiation family which negatively modulate the proliferation of OPCs and the development of oligodendrocytes . In the present study, we observed that EA inhibited the expression of PDGFR-α, the marker of OPCs, as well as decreased the number of Olig2 positive-OPCs which are the specific precursor cells of oligodendrocyte in the late phase of SAH. Moreover, EA promoted the expression of APC, the marker of mature oligodendrocytes, as well as increased the number of Olig2/APC double-staining cells, which demonstrated that EA promoted the maturation of oligodendrocytes. These results indicates that EA facilitates remyelination via promoting the OPC differentiation and oligodendrocyte maturation. Id2 works as a negative regulate transcriptive factor of oligodendrocyte by enhancing proliferation and slowing differentiation [12, 40]. Under physiological condition, SOX10 is a transcription factor that is required for lineage progression, terminal differentiation and the induction of myelination . In the present study, we observed that EA inhibited the expression of Id2 and upregulated the expression of SOX10, indicating that EA possesses the effect of modulating the transcription factor expression in OPC differentiation, which may explain the promoting effect of EA on remyelination.
Due to the deep location of white matter in the brain , the blood flow in the white matter is usually less than that in the cortex, which determines that white matter is more vulnerable to cerebral hypoperfusion. Our previous work observed that the blood flow decreased dramatically in white matter in SAH patients . Therefore, improving the CBF is a promising therapeutic method for the treatment of white matter injury. Ma et al. discovered that acupuncture increased the CBF, and preserved the myelin integrity without influencing the axons in a rat model of vascular dementia . In a clinic trial, EA treatment increased CBF and improved the outcome of SAH patients through alleviating vasospasm . Lee et al. reported that EA modulates NO and ET-1 levels of plasma after SAH . Schmahmann et al. found that EA ameliorates cerebral ischemia through anti-inflammatory effects . These studies may explain the effect of EA on improving the CBF in SAH. The present study observed a significant increase of blood flow on day 21 and day 28 after SAH, indicating that EA exerts a long-term improvement of CBF in SAH pathological process, which may also explain the protective effect of EA on white matter on the late stage of SAH.
In summary, the present study revealed that SAH induced myelin injury and cognitive deficit in rats, while EA promoted remyelination and improved cognitive function after SAH probably via promoting the differentiation of OPCs and remyelination of axons. The underlying mechanism may involve the regulation of the expression of Id2 and SOX10. Moreover, the improvement of CBF by EA was observed, which may also may explain the protective effect of EA on white matter. EA may be a potential treatment for cognitive deficit in the late phase of SAH.