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There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson’s disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

Acute ischemic stroke (AIS) and traumatic brain injury (TBI) are two severe neurological events, both being major causes of death and prolonged impairment. Their incidence continues to rise due to the global increase in the number of people at risk, representing a significant burden on those remaining impaired, their families, and society. These molecular and cellular mechanisms of both stroke and TBI present similarities that can be targeted by treatments with a multimodal mode of action, such as traditional Chinese medicine. Therefore, we performed a detailed review of the preclinical and clinical development of MLC901 (NeuroAiDTMII), a natural multi-herbal formulation targeting several biological pathways at the origin of the clinical deficits. The endogenous neurobiological processes of self-repair initiated by the brain in response to the onset of brain injury are often insufficient to achieve complete recovery of impaired functions. This review of MLC901 and its parent formulation MLC601 confirms that it amplifies the natural self-repair process of brain tissue after AIS or TBI. Following AIS and TBI where "time is brain", many patients enter the post-acute phase with their functions still impaired, a period when "the brain needs time to repair itself". The treatment goal must be to accelerate recovery as much as possible. MLC901/601 demonstrated a significant reduction by 18 months of recovery time compared to a placebo, indicating strong potential for facilitating the improvement of health outcomes and the more efficient use of healthcare resources. [ABSTRACT FROM AUTHOR]

Exosomes possess a significant role in intercellular communications. In the nervous system, various neural cells release exosomes that not only own a role in intercellular communications but also eliminate the waste of cells, maintain the myelin sheath, facilitate neurogenesis, and specifically assist in normal cognitive function. In neurological conditions including Parkinson's disease (PD), Alzheimer's disease (AD), traumatic brain injury (TBI), and stroke, exosomal cargo like miRNAs take part in the sequela of conditions and serve as a diagnostic tool of neurological disorders, too. Exosomes are not only a diagnostic tool but also their inhibition or administration from various sources like mesenchymal stem cells and serum, which have shown a worthy potential to treat multiple neurological disorders. In addition to neurodegenerative manifestations, cognitive deficiencies are an integral part of neurological diseases, and applying exosomes in improving both aspects of these diseases has been promising. This review discusses the status of exosome therapy in improving neurorestorative and cognitive function following neurological disease. [ABSTRACT FROM AUTHOR]

Progesterone (P4) is a neuroactive hormone having pleiotropic effects, supporting its pharmacological potential to treat global (cardiac-arrest-related) cerebral ischemia, a condition associated with an elevated risk of dementia. This review examines the current biochemical, morphological, and functional evidence showing the neuroprotective/neurorestorative effects of P4 against global cerebral ischemia (GCI). Experimental findings show that P4 may counteract pathophysiological mechanisms and/or regulate endogenous mechanisms of plasticity induced by GCI. According to this, P4 treatment consistently improves the performance of cognitive functions, such as learning and memory, impaired by GCI. This functional recovery is related to the significant morphological preservation of brain structures vulnerable to ischemia when the hormone is administered before and/or after a moderate ischemic episode; and with long-term adaptive plastic restoration processes of altered brain morphology when treatment is given after an episode of severe ischemia. The insights presented here may be a guide for future basic research, including the study of P4 administration schemes that focus on promoting its post-ischemia neurorestorative effect. Furthermore, considering that functional recovery is a desired endpoint of pharmacological strategies in the clinic, they could support the study of P4 treatment for decreasing dementia in patients who have suffered an episode of GCI. [ABSTRACT FROM AUTHOR]

Cell therapies have been explored to treat patients with nervous diseases for over 20 years. Even though most kinds of cell therapies demonstrated neurorestorative effects in non-randomized clinical trials; the effects of the majority type cells could not be confirmed by randomized controlled trials. In this review, clinical therapeutic results of neurorestorative cell therapies according to cellular bio-proprieties or cellular functions were introduced. Currently it was demonstrated from analysis of this review that some indications of cell therapies were not appropriate, they might be reasons why their neurorestorative effects could not be proved by multicenter, randomized, double blind, placebo-controlled clinical trials. Theoretically if one kind of cell therapy has neurorestorative effects according to its cellular bio-proprieties, it should have appropriate indications. The cell therapies with special bio-properties is promising if the indication selections are appropriate, such as olfactory ensheathing cells for chronic ischemic stroke, and their neurorestorative effects can be confirmed by higher level clinical trials of evidence-based medicine.

Ischemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise for alleviating ischemia's effects and facilitating the healing of neurological and physical functions. The aim of this systematic review was to evaluate the efficacy of nanotherapies in animal models of stroke and their potential impact on future stroke therapies. We also assessed the scientific quality of current research focused on nanoparticle-based treatments for ischemic stroke in animal models. We summarized the effectiveness of nanotherapies in these models, considering multiple factors such as their anti-inflammatory, antioxidant, and angiogenetic properties, as well as their safety and biodistribution. We conclude that the application of nanomedicines may reduce infarct size and improve neurological function post-stroke without causing significant organ toxicity. [ABSTRACT FROM AUTHOR]

Stroke is a condition characterized by sudden deprivation of blood flow to a brain region and defined by different post-injury phases, which involve various molecular and cellular cascades. At an early stage during the acute phase, fast initial cell death occurs, followed by inflammation and scarring. This is followed by a sub-acute or recovery phase when endogenous plasticity mechanisms may promote spontaneous recovery, depending on various factors that are yet to be completely understood. At later time points, stroke leads to greater neurodegeneration compared to healthy controls in both clinical and preclinical studies, this is evident during the chronic phase when recovery slows down and neurodegenerative signatures appear. Astrocytes have been studied in the context of ischemic stroke due to their role in glutamate re-uptake, as components of the neurovascular unit, as building blocks of the glial scar, and synaptic plasticity regulators. All these roles render astrocytes interesting, yet understudied players in the context of stroke-induced neurodegeneration. With this review, we provide a summary of previous research, highlight astrocytes as potential therapeutic targets, and formulate questions about the role of astrocytes in the mechanisms during the acute, sub-acute, and chronic post-stroke phases that may lead to neurorestoration or neurodegeneration.

Introduction and purpose: Ischemic stroke is one of the leading causes of death and disability worldwide. There is an urgent need to develop new treatments and diagnosis. The aim of this review is to gather current knowledge on the potential use of exosomes in the diagnosis and treatment of ischemic stroke. This review was based on available data collected in the Pub Med database and Google Scholar web search engine, using the key words: „Exosomes”, „ischemic stroke” Description of the state of knowledge: Currently, thanks to the development of knowledge about molecular processes, many studies are conducted on drugs that could limit neurodegenerative processes and support repair processes. Many of the drugs that could be used in treatment show poor penetration through the blood-brain barrier. In studies, exosomes show good penetration through the blood-brain barrier, limit neurodegenerative processes and show neuroregenerative effects. Exosomes are characterized by low immunogenicity and toxicity, and the proteins contained in them are involved in neurogenesis, anti-apoptotic processes and synaptic transmission. In addition, studies have shown exosomes inhibit autophagocytosis and reduce neuronal damage. ​ Summary: Studies performed on animal models have shown the effectiveness of exosomes in the diagnosis and treatment of ischemic stroke. Further studies are needed to determine the efficacy and safety profile of exosomes in humans.

Antiparkinsonian carotid body (CB) cell therapy has been proven to be effective in rodent and nonhuman primate models of Parkinson's disease (PD), exerting trophic protection and restoration of the dopaminergic nigrostriatal pathway. These neurotrophic actions are mediated through the release of high levels of glial-cell-line-derived neurotrophic factor (GDNF) by the CB transplant. Pilot clinical trials have also shown that CB autotransplantation can improve motor symptoms in PD patients, although its effectiveness is affected by the scarcity of the grafted tissue. Here, we analyzed the antiparkinsonian efficacy of in vitro-expanded CB dopaminergic glomus cells. Intrastriatal xenografts of rat CB neurospheres were shown to protect nigral neurons from degeneration in a chronic MPTP mouse PD model. In addition, grafts performed at the end of the neurotoxic treatment resulted in the repair of striatal dopaminergic terminals through axonal sprouting. Interestingly, both neuroprotective and reparative effects induced by in vitro-expanded CB cells were similar to those previously reported by the use of CB transplants. This action could be explained because stem-cell-derived CB neurospheres produce similar amounts of GDNF compared to native CB tissue. This study provides the first evidence that in vitro-expanded CB cells could be a clinical option for cell therapy in PD. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a neurological disorder prevalent worldwide with a high disability and mortality rate. In the clinic setting, tissue plasminogen activator (tPA) and thrombectomy could restore blood flow of the occlusion region and improve the outcomes of IS patients; however, these therapies are restricted by a narrow time window. Although several preclinical trials have revealed the molecular and cellular mechanisms underlying infarct lesions, the translatability of most findings is unsatisfactory, which contributes to the emergence of new biomaterials, such as hydrogels and nanomaterials, for the treatment of IS. Biomaterials function as structural scaffolds or are combined with other compounds to release therapeutic drugs. Biomaterial-mediated drug delivery approaches could optimize the therapeutic effects based on their brain-targeting property, biocompatibility, and functionality. This review summarizes the advances in biomaterials in the last several years, aiming to discuss the therapeutic potential of new biomaterials from the bench to bedside. The promising prospects of new biomaterials indicate the possibility of an organic combination between materialogy and medicine, which is a novel field under exploration. [ABSTRACT FROM AUTHOR]

Progesterone (P4) is a neuroactive hormone having pleiotropic effects, supporting its pharmacological potential to treat global (cardiac-arrest-related) cerebral ischemia, a condition associated with an elevated risk of dementia. This review examines the current biochemical, morphological, and functional evidence showing the neuroprotective/neurorestorative effects of P4 against global cerebral ischemia (GCI). Experimental findings show that P4 may counteract pathophysiological mechanisms and/or regulate endogenous mechanisms of plasticity induced by GCI. According to this, P4 treatment consistently improves the performance of cognitive functions, such as learning and memory, impaired by GCI. This functional recovery is related to the significant morphological preservation of brain structures vulnerable to ischemia when the hormone is administered before and/or after a moderate ischemic episode; and with long-term adaptive plastic restoration processes of altered brain morphology when treatment is given after an episode of severe ischemia. The insights presented here may be a guide for future basic research, including the study of P4 administration schemes that focus on promoting its post-ischemia neurorestorative effect. Furthermore, considering that functional recovery is a desired endpoint of pharmacological strategies in the clinic, they could support the study of P4 treatment for decreasing dementia in patients who have suffered an episode of GCI.

Spinal cord injury (SCI) is catastrophic damage for patients, their family, and society. Researchers and clinicians have been trying to find neurorestorative methods to recover their injured functions and structures. Cell therapy is one of the effective therapeutic strategies for SCI. And it can partially restore their neurological functions, which are once thought as permanent neurological deficits. Currently, cells being used therapeutically in clinic include olfactory ensheathing cells (OECs), mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), Schwann cells, and hematopoietic stem cells, cell products differentiated from embryonic stem cells, mesenchymal stem cells, induced pluripotent stem cells, and neural stem cells as well as other kinds of cells. Real world data from these cell therapies showed some benefits in some patients with SCI. Due to being affected by many factors, the therapeutic results of some kinds of cells are contradictory and it is hard to compare effects among different types of cells. According to the data of cell therapies, OEC, MNC and MSC transplantation are applied for patients in majority percentage of cases, and OEC transplantation had a higher percentage of benefits. In next step, under the unified standard of cell preparation and quality control as well as the guidelines of clinical cell application, each kind of cells including OECs should be studied using prospective, multicenter, double-blind or observing-blind, placebo-control, randomized studies for SCI patients with different level of injury and chronicity.

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson’s disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson’s disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in βIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson’s disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Brain ischemia affects all ages, from neonates to the elderly population, and is a leading cause of mortality and morbidity. Multiple preclinical rodent models involving different ages have been developed to investigate the effect of ischemia during different times of key brain maturation events. Traditional models of developmental brain ischemia have focused on rodents at postnatal day 7–10, though emerging models in juvenile rodents (postnatal days 17–25) indicate that there may be fundamental differences in neuronal injury and functional outcomes following focal or global cerebral ischemia at different developmental ages, as well as in adults. Here, we consider the timing of injury in terms of excitation/inhibition balance, oxidative stress, inflammatory responses, blood brain barrier integrity, and white matter injury. Finally, we review translational strategies to improve function after ischemic brain injury, including new ideas regarding neurorestoration, or neural repair strategies that restore plasticity, at delayed time points after ischemia. [ABSTRACT FROM AUTHOR]

Currently, most cellular therapeutic effects for nervous diseases cannot be proven in a multicenter, randomized, double-blind placebo-control clinical trials, except for a few kinds of cells such as olfactory ensheathing cells. These cells show significant improvements in functional recovery and quality of life for patients with chronic ischemic stroke. Also, olfactory neuron transplantation has promising neurorestorative effects on patients with vascular dementia. Human olfactory neuroepithelium can spontaneously and sustainably regenerate or produce new olfactory neurons and glial cell types for decades or a lifetime. The neurorestorative mechanisms of olfactory ensheathing cells are well known; however, little is known about the neurorestorative mechanisms of olfactory neurons. Therefore, I hypothesize that the neurorestorative mechanisms of olfactory neurons after transplantation: (1) can well migrate where they are needed and become local functional neurons, as they need to compensate or replace; (2) must be regulated by some special molecular factors to elongate their axons, modulate or direct synapses to correctly recognize and connect the target cells, and integrate functions. Based on olfactory neuroepithelium cells displaying the special characterization, neurorestorative mechanisms, clinical therapeutic achievements, and hypotheses of effective mechanisms, they (olfactory ensheathing cells and olfactory neurons) may be the most efficient instruments of neurorestoration.

Considering its marked life-threatening and (not seldom: severe and/or permanent) disabling, potential, plus the overall medico-psycho-socio-economic tough burden it represents for the affected persons, their families and the community, the cerebrovascular accident (CVA)—including with the, by far more frequent, ischemic type—is subject to considerable scientific research efforts that aim (if possible) at eliminating the stroke induced lesions, and consist, as well, in ambitious—but still poorly transferable into medical practice—goals such as brain neuroregeneration and/or repair, within related corollary/upshot of neurorestoration. We have conducted, in this respect, a systematic and synthetic literature review, following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” concept. Accordingly, we have interrogated five internationally renowned medical data bases: Elsevier, NCBI/PubMed, NCBI/PMC, PEDro, and ISI Web of Knowledge/Science (the last one to check whether the initially identified articles are published in ISI indexed journals), based on a large (details in the body text) number of most appropriate, to our knowledge, key word combinations/“syntaxes”—used contextually—and subsequently fulfilling the related, on five steps, filtering/selection methodology. We have thereby selected 114 fully eligible (of which contributive: 83—see further) papers; at the same time, additionally, we have enhanced our documentation—basically, but not exclusively, for the introductive part of this work (see further)—with bibliographic resources, overall connected to our subject, identified in the literature within a non-standardized search. It appears that the opportunity window for morph-functional recovery after stroke is larger than previously thought, actually being considered that brain neurorestoration/repair could occur, and therefore be expected, in later stages than in earlier ones, although, in this context, the number of cases possibly benefitting (for instance after physical and/or cognitive rehabilitation—including with magnetic or direct current transcranial stimulation) is quite small and with more or less conflicting, related outcomes, in the literature. Moreover, applying especially high intense, solicitating, rehabilitation interventions, in early stages post (including ischemic) stroke could even worsen the functional evolution. Accordingly, for clarifications and validation of more unitary points of view, continuing and boosting research efforts in this complex, interdisciplinary domain, is necessary. Until finding (if ever) effective modalities to cure the lesions of the central nervous system (CNS)—including post ischemic stroke—it is reasonable and recommendable—based on rigorous methodologies—the avail of combined ways: physiatric, pharmacologic, possibly also bio-technologic. On a different note, but however connected to our subject: periodic related systematic, synthetic literature reviews reappraisals are warranted and welcome.

In addition to genetic information, environmental factors play an important role in the structure and function of nervous system and the occurrence and development of some nervous system diseases. Enriched environment (EE) can not only promote normal neural development through enhancing neuroplasticity but also play a nerve repair role in restoring functional activities during CNS injury by morphological and cellular and molecular adaptations in the brain. Different stages of development after birth respond to the environment to varying degrees. Therefore, we systematically review the pro-developmental and anti-stress value of EE during pregnancy, pre- weaning, and "adolescence" and analyze the difference in the effects of EE and its sub-components, especially with physical exercise. In our exploration of potential mechanisms that promote neurodevelopment, we have found that not all sub-components exert maximum value throughout the developmental phase, such as animals that do not respond to physical activity before weaning, and that EE is not superior to its sub-components in all respects. EE affects the developing and adult brain, resulting in some neuroplastic changes in the microscopic and macroscopic anatomy, finally contributing to enhanced learning and memory capacity. These positive promoting influences are particularly prominent regarding neural repair after neurobiological disorders. Taking cerebral ischemia as an example, we analyzed the molecular mediators of EE promoting repair from various dimensions. We found that EE does not always lead to positive effects on nerve repair, such as infarct size. In view of the classic issues such as standardization and relativity of EE have been thoroughly discussed, we finally focus on analyzing the essentiality of the time window of EE action and clinical translation in order to devote to the future research direction of EE and rapid and reasonable clinical application. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders of the central nervous system (CNS) and brain traumatic insults are characterized by complex overlapping pathophysiological alterations encompassing neuroinflammation, alterations of synaptic functions, oxidative stress, and progressive neurodegeneration that eventually lead to irreversible motor and cognitive dysfunctions. A single pharmacological approach is unlikely to provide a complementary set of molecular therapeutic actions suitable to resolve these complex pathologies. Recent preclinical data are providing evidence-based scientific rationales to support biotherapies based on administering neurotrophic factors and extracellular vesicles present in the lysates of human platelets collected from healthy donors to the brain. Here, we present the most recent findings on the composition of the platelet proteome that can activate complementary signaling pathways in vivo to trigger neuroprotection, synapse protection, anti-inflammation, antioxidation, and neurorestoration. We also report experimental data where the administration of human platelet lysates (HPL) was safe and resulted in beneficial neuroprotective effects in established rodent models of neurodegenerative diseases such as Parkinson’s disease, Alzheimer's disease, traumatic brain injury, and stroke. Platelet-based biotherapies, prepared from collected platelet concentrates (PC), are emerging as a novel pragmatic and accessible translational therapeutic strategy for treating neurological diseases. Based on this assumption, we further elaborated on various clinical, manufacturing, and regulatory issues that need to be addressed to ensure the ethical supply, quality, and safety of HPL preparations for treating neurodegenerative and traumatic pathologies of the CNS. HPL made from PC may become a unique approach for scientifically based treatments of neurological disorders readily accessible in low-, middle-, and high-income countries. [ABSTRACT FROM AUTHOR]

The transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) can promote hypoxic-ischemic brain damage (HIBD) nerve repair, but finding suitable seed cells to optimize transplantation and improve treatment efficiency is an urgent problem to be solved. In this study, we induced hUC-MSCs into dedifferentiated hUC-MSCs (De-hUC-MSCs), and the morphology, stem cell surface markers, proliferation and tri-directional differentiation ability of the De-hUC-MSCs and hUC-MSCs were detected. A whole-gene chip was utilized for genome cluster, gene ontology and KEGG pathway analyses of differentially expressed genes. De-hUC-MSCs were transplanted into HIBD rats, and behavioral experiments and immunofluorescence assays were used to assess the therapeutic effect. A lentivirus vector for human stromal cell-derived factor-1 (hSDF-1α) was constructed, and the role of hSDF-1α in the neuroprotective effect and mechanism of De-hUC-MSCs was verified. De-hUC-MSCs displayed similar cell morphology, stem cell surface marker expression, cell proliferation and even three-dimensional differentiation ability as hUC-MSCs but exhibited greater treatment potential in vivo. The reprogramming mechanism of hSDF-1α participated in the dedifferentiation process. By successfully constructing a stable hSDF-1α cell line, we found that De-hUC-MSCs might participate in nerve repair through the hSDF-1α/CXCR4/PI3K/Akt pathway. De-hUC-MSCs reprogramming of endogenous hSDF-1α expression may mediate the hSDF-1α/CXCR4/PI3K/Akt pathway involved in nerve repair in HIBD rats.

Sildenafil is a recognized treatment for patients suffering from erectile dysfunction and pulmonary hypertension. However, new evidence suggests that it may have a neuroprotective and a neurorestorative role in the central nervous system of both adults and neonates. Phosphodiesterase type 5—the target of sildenafil—is distributed in many cells throughout the body, including neurons and glial cells. This study is a comprehensive review of the demonstrated effects of sildenafil on the brain with respect to its function, extent of injury, neurons, neuroinflammation, myelination, and cerebral vessels. [ABSTRACT FROM AUTHOR]

Chronic disorders of consciousness (DOC) include the vegetative state and the minimally consciousness state. The DOC diagnosis mainly relies on the evaluation of clinical behavioral scales, electrophysiological testing, and neuroimaging examinations. No specifically effective neurorestorative methods for chronic DOC currently exist. Any valuable exploration therapies of being able to repair functions and/or structures in the consciousness loop (e.g., drugs, hyperbaric medicines, noninvasive neurostimulation, sensory and environmental stimulation, invasive neuromodulation therapy, and cell transplantation) may become effective neurorestorative strategies for chronic DOC. In the viewpoint of Neurorestoratology, this guideline proposes the diagnostic and neurorestorative therapeutic suggestions and future exploration direction for this disease following the review of the existing treatment exploration achievements for chronic DOC.

Treatment of spinal cord injury (SCI) remains challenging. Considering the rapid developments in neurorestorative therapies for SCI, we have revised and updated the Clinical Therapeutic Guidelines for Neurorestoration in Spinal Cord Injury (2016 Chinese version) of the Chinese Association of Neurorestoratology (Preparatory) and China Committee of International Association of Neurorestoratology. Treatment of SCI is a systematic multimodal process that aims to improve survival and restore neurological function. These guidelines cover real-world comprehensive neurorestorative management of acute, subacute, and chronic SCI and include assessment and diagnosis, pre-hospital first aid, treatment, rehabilitation, and complication management.

The neurorestorative efficacy of human platelet lysates in neurodegenerative disorders is still under investigation. Platelets prepared from standard and pathogen reduced platelet concentrates were pelletized, washed, concentrated, and subjected to freeze-thawing. The lysate was heated to 56°C for 30 min and characterized. Toxicity was evaluated using SH-SY5Y neuroblastoma, BV-2 microglial, and EA-hy926 endothelial cells. Inflammatory activity was tested by examining tumor necrosis factor (TNF) and cyclooxygenase (COX)-2 expressions by BV-2 microglia with or without stimulation by lipopolysaccharides (LPS). The capacity to stimulate wound healing was evaluated by a scratch assay, and the capacity to differentiate SH-SY5Y into neurons was also examined. Platelet lysates contained a range of neurotrophins. They were not toxic to SH-SY5Y, EA-hy926, or BV-2 cells, did not induce the expression of TNF or COX-2 inflammatory markers by BV-2 microglia, and decreased inflammation after LPS stimulation. They stimulated the wound closure in the scratch assay and induced SH-SY5Y differentiation as revealed by the increased length of neurites as well as β3-tubulin and neurofilament staining. These data confirm the therapeutic potential of platelet lysates in the treatment of disorders of the central nervous system and support further evaluation as novel neurorestorative biotherapy in preclinical models.

Several therapies have shown obvious effects on structural conservation contributing to motor functional recovery after spinal cord injury (SCI). Nevertheless, neither strategy has achieved a convincing effect. We purposed a combined therapy of immunomodulatory peptides that individually have shown significant effects on motor functional recovery in rats with SCI. The objective of this study was to investigate the effects of the combined therapy of monocyte locomotion inhibitor factor (MLIF), A91 peptide, and glutathione monoethyl ester (GSH-MEE) on chronic-stage spinal cord injury. Female Sprague-Dawley rats underwent a laminectomy of the T9 vertebra and a moderate contusion. Six groups were included: sham, PBS, MLIF + A91, MLIF + GSH-MEE, A91 + GSH-MEE, and MLIF + A91 + GSH-MEE. Two months after injury, motor functional recovery was evaluated using the open field test. Parenchyma and white matter preservation was evaluated using hematoxylin & eosin staining and Luxol Fast Blue staining, respectively. The number of motoneurons in the ventral horn and the number of axonal fibers were determined using hematoxylin & eosin staining and immunohistochemistry, respectively. Collagen deposition was evaluated using Masson’s trichrome staining. The combined therapy of MLIF, A91, and GSH-MEE greatly contributed to motor functional recovery and preservation of the medullary parenchyma, white matter, motoneurons, and axonal fibres, and reduced the deposition of collagen in the lesioned area. The combined therapy of MLIF, A91, and GSH-MEE preserved spinal cord tissue integrity and promoted motor functional recovery of rats after SCI. This study was approved by the National Commission for Scientific Research on Bioethics and Biosafety of the Instituto Mexicano del Seguro Social under registration number R-2015-785-116 (approval date November 30, 2015) and R-2017-3603-33 (approval date June 5, 2017).

Current experimental stroke research has evolved to focus on detailed understanding of the brain’s self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1–7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.

Sildenafil is a recognized treatment for patients suffering from erectile dysfunction and pulmonary hypertension. However, new evidence suggests that it may have a neuroprotective and a neurorestorative role in the central nervous system of both adults and neonates. Phosphodiesterase type 5—the target of sildenafil—is distributed in many cells throughout the body, including neurons and glial cells. This study is a comprehensive review of the demonstrated effects of sildenafil on the brain with respect to its function, extent of injury, neurons, neuroinflammation, myelination, and cerebral vessels.

Stroke is the main cause of death and disability among Chinese, and neurorestoration is an effective therapeutic strategy for patients with stroke. In recent years, many achievements have been made in stroke neurorestoration, but viewpoints for managing stroke vary per discipline. In order to promote standardization of diagnosis and treatment for stroke neurorestoration, the Chinese Association of Neurorestoratology (CANR; Preparatory) and China Committee of International Association of Neurorestoratology (IANR-China Committee) organized professional experts in the field to integrate fragmented neurorestorative methods and establish clinical diagnostic and therapeutic guidelines for stroke neurorestoration. This guideline includes the diagnosis and staging of stroke and therapeutic recommendations for neurorestoration at different stages of stroke in order to improve survival and quality of life of stroke patients.

Currently, there are many different standards for the quality control of olfactory ensheathing cell (OEC) culture prepared from human olfactory bulb and mucosa. It is challenging to compare the clinical results of OEC treatment from different hospitals. Based on various standards, the Chinese Association of Neurorestoratology (CANR; Preparatory) and China Committee of International Association of Neurorestoratology (IANR-China Committee) organized professional experts in this field to evaluate the data and develop a standard for clinical applications, including donor evaluation, sample collection, cell culture, cell testing, packaging labels, storage, transportation, and quality control of intermediate/finished cell products, as well as training and management procedures for laboratory operators, the use and management of materials and equipment, and routine maintenance of a clean environment. These standards apply to the quality and control of OEC culture using human olfactory bulb and mucosa as the sample source for the member units of the CANR (Preparatory) and IANR-China Committee. It serves as a reference for physicians around the world who perform OEC clinical applications. This standard represents the minimum required standards for quality control when performing clinical-grade OEC cultures in clinical neurorestorative treatments.

Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.

Spinal cord injury (SCI) commonly results in permanent loss of motor, sensory, and autonomic function. Recent clinical studies have shown that epidural spinal cord stimulation may provide a beneficial adjunct for restoring lower extremity and other neurological functions. Herein, we review the recent clinical advances of lumbosacral epidural stimulation for restoration of sensorimotor function in individuals with motor complete SCI and we discuss the putative neural pathways involved in this promising neurorehabilitative approach. We focus on three main sections: review recent clinical results for locomotor restoration in complete SCI; discuss the contemporary understanding of electrical neuromodulation and signal transduction pathways involved in spinal locomotor networks; and review current challenges of motor system modulation and future directions toward integrative neurorestoration. The current understanding is that initial depolarization occurs at the level of large diameter dorsal root proprioceptive afferents that when integrated with interneuronal and latent residual supraspinal translesional connections can recruit locomotor centers and augment downstream motor units. Spinal epidural stimulation can initiate excitability changes in spinal networks and supraspinal networks. Different stimulation parameters can facilitate standing or stepping, and it may also have potential for augmenting myriad other sensorimotor and autonomic functions. More comprehensive investigation of the mechanisms that mediate the transformation of dysfunctional spinal networks to higher functional states with a greater focus on integrated systems-based control system may reveal the key mechanisms underlying neurological augmentation and motor restoration after severe paralysis. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at ∼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment. [ABSTRACT FROM AUTHOR]

Despite remarkable advances in the treatment of numerous medical conditions, neurological disease and injury remains an outstanding challenge and cause of disability worldwide. The decreased regenerative capacity and extreme complexity and heterogeneity of nervous tissue, in particular the brain, and the fact that the brain remains the least understood organ, have hampered our ability to provide definitive treatments for prevalent conditions such as stroke. Stroke is the second‐leading cause of death worldwide, and the nervous system is intimately involved in other prevalent conditions including ischemic heart disease, diabetes mellitus, and hypertension. Advances in neuromodulation, electroceuticals, microsurgical techniques, optogenetics, brain–computer interfaces, and autologous constructs offer potential solutions to address the otherwise permanent neurological deficits of stroke and other conditions. Here we review these various approaches to build an "artificial nervous system" that could restore function and independence in people living with these conditions. We focus on stroke both because it is the leading cause of neurological disability worldwide and because we anticipate that advances in the reversal of stroke‐related deficits will have ripple effects benefiting people with other neurological conditions including spinal cord injury, traumatic brain injury, ALS, and muscular dystrophy. [ABSTRACT FROM AUTHOR]

Cell therapy has been shown to be a crucial clinical therapeutic option for central nervous system diseases or damage. Promoting standardization of clinical cell therapy procedures is essential for professional associations devoted to cell therapy. The International Association of Neurorestoratology (IANR) and the Chinese Association of Neurorestoratology (CANR; Preparatory) collaborated to release Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017) in 2018. Due to recent advances and achievements in clinical cell therapy worldwide in recent years, IANR and CANR have renewed and updated the guidelines. Except for the requirements of equipment, personnel, and ethics, these revised guidelines include cell type nomenclature, cell quality control, cell types in clinical application, minimal suggested cellular doses, patient-informed consent, indications and contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, the policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility. IANR/CANR recommends that all clinical practitioners follow these cellular therapy guidelines. These guidelines provide references of better cell types, doses, routes, and therapeutic timing windows in different diseases.

There are a few systematical studies on the programme management for post-ischemic stroke using a specific template as the template for intervention description and replication (TIDieR) to improve outcomes of an intervention. The present study aimed to measure the impact of neurorestoration as a programme management using motor learning apply with a validated TIDieR that was specifically designed for post-ischemic stroke patients. A pre-post-test randomized control trial was conducted on 64 post-acute ischemic stroke patients who had the inclusion criteria in a week. Control groups (n = 32) received the routine mobilization with a conventional method based on hospital procedures, while treatment groups (n = 32) underwent structured motor learning with a modified TIDieR. Motor learning improvement was considered as a functional ability that was measured by applying the Barthel Index. Statistical analysis was performed using the Independent Samples t-test. The improved functional abilities (mean ± SD) were 27.41 ± 20.10 and 41.66 ± 21.66 in control and treatment groups respectively (P = 0.008). The improvement of functional ability in treatment groups was approximately 1.5 times higher than the control groups. Programme management using motor learning through the TIDieR improved functional abilities of post-ischemic stroke patients compared to the conventional method. [ABSTRACT FROM AUTHOR]

The neurorestorative efficacy of human platelet lysates in neurodegenerative disorders is still under investigation. Platelets prepared from standard and pathogen reduced platelet concentrates were pelletized, washed, concentrated, and subjected to freeze-thawing. The lysate was heated to 56°C for 30 min and characterized. Toxicity was evaluated using SH-SY5Y neuroblastoma, BV-2 microglial, and EA-hy926 endothelial cells. Inflammatory activity was tested by examining tumor necrosis factor (TNF) and cyclooxygenase (COX)-2 expressions by BV-2 microglia with or without stimulation by lipopolysaccharides (LPS). The capacity to stimulate wound healing was evaluated by a scratch assay, and the capacity to differentiate SH-SY5Y into neurons was also examined. Platelet lysates contained a range of neurotrophins. They were not toxic to SH-SY5Y, EA-hy926, or BV-2 cells, did not induce the expression of TNF or COX-2 inflammatory markers by BV-2 microglia, and decreased inflammation after LPS stimulation. They stimulated the wound closure in the scratch assay and induced SH-SY5Y differentiation as revealed by the increased length of neurites as well as β3-tubulin and neurofilament staining. These data confirm the therapeutic potential of platelet lysates in the treatment of disorders of the central nervous system and support further evaluation as novel neurorestorative biotherapy in preclinical models. [ABSTRACT FROM AUTHOR]

The netrin‐1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin‐1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin‐1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin‐1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin‐1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of netrin‐1 in different animal models of PD. We demonstrate that both overexpression of netrin‐1 and brain administration of recombinant netrin‐1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin‐1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin‐1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin‐1 signaling in PD. SYNOPSIS: This study shows, using various in vivo approaches, a novel role for netrin‐1 as a key regulator of adult nigral dopamine neuron maintenance and highlights the therapeutic potential of targeting netrin‐1 signalling in Parkinson's disease. Netrin‐1 is required for the maintenance of adult dopamine neurons in the substantia nigraLoss of netrin‐1 in the substantia nigra induces receptor cleavage and apoptotic cell death of dopamine neuronsNetrin‐1 is protective and neurorestorative in various models of Parkinson's disease [ABSTRACT FROM AUTHOR]

Aim: Vasculotide (VT), an angiopoietin‐1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long‐term neurological outcome after stroke in T1DM rats. Methods: Male Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages. Results: Treatment of T1DM‐stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM‐stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM‐stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP‐1, endothelin‐1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non‐treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP‐1 in macrophages subjected to LPS activation and significantly decreases IL‐1β and MMP9 expression in PCN subjected to ischemia under HG conditions. Conclusion: Delayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is the leading cause of disability in the western world, assuming a high socio-economic cost. One of the most used strategies in the last decade has been biomaterials, which have been initially used with a structural support function. They have been perfected, different compounds have been combined, and they have been used together with cell therapy or controlled release chemical compounds. This double function has driven them as potential candidates for the chronic treatment of IS. In fact, the most developed are in different phases of clinical trial. In this review, we will show the ischemic scenario and address the most important criteria to achieve a successful neuroreparation from the point of view of biomaterials. The spontaneous processes that are activated and how to enhance them is one of the keys that contribute to the success of the therapeutic approach. In addition, the different routes of administration and how they affect the design of biomaterials are analyzed. Future perspectives show where this broad scientific field is heading, which advances every day with the help of technology and advanced therapies.