Signaling Molecular Generators Regulate Neural Plasticity For The Treatment Of Neurological Disorders

The high burden of disability and deaths caused by neurological disorders has become a global public health challenge.However,the complexity of the nervous system makes it difficult for the existing treatments to achieve satisfactory effects.Therefore,novel and effective therapeutic strategies for the prevention and treatment of various neurological disorders are urgently needed to be developed.The changes occurring in the nervous system under pathological conditions are the essence of neurological disorders,and neural plasticity is the underlying mechanism of these changes.Thus,directionally regulating neural plasticity can fundamentally influence the process of neurological disorders for providing effective prevention and treatment.The neural plasticity requires long-term,repetitive and precise modulation,which can be realized by a variety of signaling molecules through influencing the internal and external environment of neurons.Thus,this thesis focuses on the signaling molecules mediated regulation of neural plasticity.A series of novel signaling molecule generators are designed and prepared based on functional nanomaterials.The feasibility and universality of signal molecular generators to regulate neural plasticity in the treatment of various neurological disorders has been systematically investigated.This thesis mainly includes the following three aspects:1.Exogenous stimulus-responsive signaling molecular generator enhances neural plasticity for the recovery of spinal cord injury（SCI）.The complex pathological environment of SCI severely limits the compensatory recovery induced by neural plasticity after injury,which causing the repair of SCI is difficult.Also,because of limited efficacy and single function,the existing drugs are hard to treat SCI effectively.In this study,based on the positive role of neural plasticity in promoting nerve regeneration in SCI,a near-infrared（NIR）controlled nitric oxide（NO）signaling molecule generator（UCZNs）has been designed and synthesized to enhance neural plasticity for the repair of SCI.The UCZNs can release NO upon deep-penetrated NIR stimulation,and recover the SCI from the following two aspects:（1）Due to its fat-soluble and neuroprotection,NO can diffuse freely across any physiological barrier to remove oxidative stress and inhibit inflammatory for neuroprotection,which removes the obstacle of the complex pathological environment on neural plasticity;（2）NO can improve neural plasticity via activating the neural intrinsic mechanism,which promotes nerve regeneration.By promoting neural plasticity through the two aspects above,the UCZNs can repair the SCI.The experiments in vitro and in vivo show that the UCZNs can reverse the pathological environment of SCI,as well as significantly promote the growth of neurons.Thus,the UCZNs not only perform effective treatment of SCI in zebrafish and rats,but also improve the motor function of SCI rats significantly.This study breaks through the bottleneck problems of SCI recovery and overcomes the limitations of existing SCI drugs,which provides a universal treatment strategy for the treatment of more nerve injury diseases.2.Endogenous stimulus-responsive signal molecular generator enhances neural plasticity for the prevention and treatment of ischemia-reperfusion spinal cord injury.Ischemia-reperfusion injury（IRI）not only is the direct cause of SCI,but also is the key cause of secondary injury after SCI.IRI is characterized by severe oxidative stress and inflammatory reactions,which severely restricts the positive effect of neural plasticity after SCI.Focused on IRI,the common pathological feature of various SCI,this study designs an endogenous stimulus-responsive signaling molecular generator（Zn S nanoparticles,ZnSNPs）.ZnSNPs can release Zn²⁺and H₂S slowly in response to the IRI-induced p H decrease for preventing and treating SCI by reversing IRI.This strategy plays its functions from the following two aspects:（1）H₂S released from signaling molecule generator can clean IRI-induced oxidative stress and inflammatory,which prevents the development of IRI and eliminates the obstacle of the pathological environment on neural plasticity;（2）H₂S and Zn²⁺can increase the expression and synthesis of BDNF by synergistically activating the CREB/BDNF pathway,which enhances the positive effect of neural plasticity and promotes neural regeneration.The experiments in vitro and in vivo show that ZnSNPs can significantly promote neuronal growth and mechanical injury repair,effectively prevent SCI caused by foreseeable surgical complications as well as treat unexpected traumatic SCI.This study reverses the IRI-induced pathological environment and improves the positive effect of neural plasticity by the combination of the rapid chemical reaction and long-term biological regulation,which provides a novel treatment strategy for a wider range of IRI related diseases.3.Dynamic reactive signaling molecular generator inhibits neural plasticity for the prevention and treatment of chronic pains.The treatment of chronic pain has great limitations because of the lack of effective analgesics.The common problems of current analgesics are insufficient analgesic effect,short effective time,large side effects and easy to produce tolerance or addiction.The formation of central sensitization caused by excessive stress of neural plasticity is the source of chronic pains.However,the prevention and reversal of central sensitization are still unsolved problems in the treatment of chronic pains.Thus,this study designed and synthesized the Mg²⁺signaling molecular generator（Mg B₂ nanoparticles,MBNPs）with the characteristic of dynamic reactions to inhibit central sensitization and chronic pain.MBNPs can decompose dynamically in response to the p H decrease,and slowly release Mg²⁺,boron hydride nanosheet（BH）and H₂.This strategy performs analgesic effects from the following two aspects:（1）Mg²⁺can directly inhibit neuronal excitability by blocking the Ca²⁺channel,while BH can reduce neuronal excitability by restraining the mobility of extracellular cations.Mg²⁺and BH can quickly restore the inhibitory mechanism of neuronal excitability synergistically and cuts off the transmission of neural activity,which inhibits the development of neural plasticity;（2）The strong reducibility of MBNPs and their reduction products（BH and H₂）helps to scavenge ROS and reduce inflammatory reactions,which cleans the pathological stimulus for preventing excessive stress of neural plasticity.By the two aspects above,MBNPs can achieve effective treatment of chronic pains.The experiments in vitro and in vivo show that compared with morphine,the most effective analgesic in clinical,MBNPs perform comparable analgesic effects and prolong analgesic time.Meanwhile,MBNPs also have functions that morphine cannot achieve,including inhibition of central sensitization,treatment of neuropathological pain,prevention of predictable chemotherapy-induced pain,and free of tolerance or addiction.This study focuses on the negative role of neuroplasticity in chronic pains and breaks down the bottleneck problem of chronic pain treatment by inhibiting the development of neural plasticity,which inspires the drug development of chronic pain treatment.