Letter from the editors-in-chief, Neural Regeneration Research 2020 15(1):5-5

Classic axon guidance molecules control correct nerve bridge tissue formation and precise axon regeneration Xin-Peng Dun, David B Parkinson Neural Regeneration Research 2020 15(1):6-9 The peripheral nervous system has an astonishing ability to regenerate following a compression or crush injury; however, the potential for full repair following a transection injury is much less. Currently, the major clinical challenge for peripheral nerve repair come from long gaps between the proximal and distal nerve stumps, which prevent regenerating axons reaching the distal nerve. Precise axon targeting during nervous system development is controlled by families of axon guidance molecules including Netrins, Slits, Ephrins and Semaphorins. Several recent studies have indicated key roles of Netrin1, Slit3 and EphrinB2 signalling in controlling the formation of new nerve bridge tissue and precise axon regeneration after peripheral nerve transection injury. Inside the nerve bridge, nerve fibroblasts express EphrinB2 while migrating Schwann cells express the receptor EphB2. EphrinB2/EphB2 signalling between nerve fibroblasts and migrating Schwann cells is required for Sox2 upregulation in Schwann cells and the formation of Schwann cell cords within the nerve bridge to allow directional axon growth to the distal nerve stump. Macrophages in the outermost layer of the nerve bridge express Slit3 while migrating Schwann cells and regenerating axons express the receptor Robo1; within Schwann cells, Robo1 expression is also Sox2-dependent. Slit3/Robo1 signalling is required to keep migrating Schwann cells and regenerating axons inside the nerve bridge. In addition to the Slit3/Robo1 signalling system, migrating Schwann cells also express Netrin1 and regenerating axons express the DCC receptor. It appears that migrating Schwann cells could also use Netrin1 as a guidance cue to direct regenerating axons across the peripheral nerve gap. Engineered neural tissues have been suggested as promising alternatives for the repair of large peripheral nerve gaps. Therefore, understanding the function of classic axon guidance molecules in nerve bridge formation and their roles in axon regeneration could be highly beneficial in developing engineered neural tissue for more effective peripheral nerve repair.

Axon regeneration induced by environmental enrichment- epigenetic mechanisms Bor Luen Tang Neural Regeneration Research 2020 15(1):10-15 Environmental enrichment is known to be beneficial for cognitive improvement. In many animal models of neurological disorders and brain injury, EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury. The exact underlying mechanism for these phenomena has been unclear. Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+ influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation. This, in turn, increases the expression of pro-regeneration genes and promotes axonal regeneration. This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light. The other prominent mechanisms, albeit not yet directly associated with environmental enrichment, include DNA methylation/demethylation and N6-methyladenosine modification of transcripts. In this brief review, I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration, and discuss the mechanism and pathways involved. I further speculate on the implications of the findings, in conjunction with the other epigenetic mechanisms, that could be harness to promote axon regeneration upon injury.

Angiogenesis and neuronal remodeling after ischemic stroke Masahiro Hatakeyama, Itaru Ninomiya, Masato Kanazawa Neural Regeneration Research 2020 15(1):16-19 Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models.This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets.

δ-Opioid receptor as a potential therapeutic target for ischemic stroke Kalpana Subedi, Hongmin Wang Neural Regeneration Research 2020 15(1):20-24 Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels. Despite having advancement in the use of thrombolytic and clot removal medicine, significant numbers of stroke patients are still left out without option for treatment. In this review, we summarize recent research work on the activation of δ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury. Moreover, as activation of δ-opioid receptor by a non-peptidic δ-opioid receptor agonist also modulates the expression, maturation and processing of amyloid precursor protein and β-secretase activity, the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed.

Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging Hiroshi Nakanishi Neural Regeneration Research 2020 15(1):25-29 Interleukin-1β is a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease, Parkinson’s disease, stroke and persistent pain. Activated microglia are the main cellular source of interleukin-1β in the brain. Cathepsin B is associated with the production and secretion of interleukin-1β through pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes. The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A, which can stabilize mitochondrial DNA. Therefore, microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging. Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.

Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer’s disease therapy Alejandro Romero, José Marco-Contelles, Eva Ramos Neural Regeneration Research 2020 15(1):30-35 There is no effective treatment to face Alzheimer’s disease complexity. Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression. In this context, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234) has been tested achieving promising results. ASS234 has demonstrated to cross the blood-brain barrier in vivo, and a good in silico safety profile being less toxic than donepezil. Besides, ASS234 reversibly inhibits human acetyl- and butyryl-cholinesterase, and irreversibly inhibits human monoamine oxidase A and B. Moreover, this multitarget molecule has antioxidant and neuroprotective properties, and inhibits Αβ1–42 and Αβ1–40 self-aggregation. Inquiring about the mechanism of action, several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site (Wnt) family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes. Finally, in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus, ameliorating scopolamine-induced learning deficits. Here we gather the information regarding ASS234 evaluated so far, showing its ability to face different targets, necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.

Stem cell therapy for Parkinson’s disease: safety and modeling Theo Stoddard-Bennett, Renee Reijo Pera Neural Regeneration Research 2020 15(1):36-40 For decades, clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease, but no treatment currently can slow or even stop the progression of this localized neurodegeneration. Fortunately, sparked by the genetic revolution, stem cell reprogramming research and the advancing capabilities of personalization in medicine enable forward-thinking to unprecedented patient-specific modeling and cell therapies for Parkinson’s disease using induced pluripotent stem cells (iPSCs). In addition to modeling Parkinson’s disease more accurately than chemically-induced animal models, patient-specific stem cell lines can be created, elucidating the effects of genetic susceptibility and sub-populations’ differing responses to in vitro treatments. Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients. In hopes of finally slowing the progression of Parkinson’s disease or re-establishing function, iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for Parkinson’s disease. With relatively localized neural degeneration, similar to spinal column injury, Parkinson’s disease presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease. Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis. Precautions, therefore, must be taken to ensure cell line quality before transplantation. While cell quality can be quantified using a number of assays, a yielding a high percentage of therapeutically relevant dopaminergic neurons, minimal de novo genetic mutations, and standard chromosomal structure is of the utmost importance. Current techniques focus on iPSCs because they can be matched with donors using human leukocyte antigens, thereby reducing the severity and risk of immune rejection. In August of 2018, researchers in Kyoto, Japan embarked on the first human clinical trial using iPSC cell therapy transplantation for patients with moderate Parkinson’s disease. Transplantation of many cell sources has already proven to reduce Parkinson’s disease symptoms in mouse and primate models. Here we discuss the history and implications for cell therapy for Parkinson’s disease, as well as the necessary safety standards needed for using iPSC transplantation to slow or halt the progression of Parkinson’s disease.

Selective serotonin reuptake inhibitors and Alzheimer’s disease Bernadette Mdawar, Elias Ghossoub, Rita Khoury Neural Regeneration Research 2020 15(1):41-46 Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

tRNA cleavage: a new insight Sherif Rashad, Kuniyasu Niizuma, Teiji Tominaga Neural Regeneration Research 2020 15(1):47-52 Over the past decades, tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others, holding more than half of all modifications occurring in RNA molecules. Moreover, tRNA was discovered to be a source of various small noncoding RNA species, such as the stress induced angiogenin cleaved tRNA halves (tiRNA) or the miRNA like tRNA derived fragments. tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species, including mammals. Under cellular stress conditions, tRNA undergoes conformational changes and angiogenin cleaves it into 3′ and 5′ halves. 5′tiRNA halves were shown to repress protein translations. tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis, however some data hints to the opposite; that tiRNA are cytotoxic or at least related to apoptosis initiation. tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria. In this review, we will highlight the biology of tRNA cleavage, show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research.