Trenton Lippert

Utilizing Delta Opioid Receptors and Peptides for Cytoprotection: Implications in Stroke and Other Neurological Disorders

The opioid system has been elucidated as a potential target for therapy in a variety of neurological disorders including stroke. Delta opioid receptors have been revealed to pose an especially compelling biological function for new neuroprotective therapies. Two distinct therapeutic mechanisms have been characterized for delta opioid receptors, namely, these receptors aid in maintaining ionic homeostasis and initiate endogenous neuroprotective pathways. Specific agonists of delta opioid receptors, such as (D-Ala2, D-Leu5) enkephalin (DADLE), have displayed the ability to promote neuronal survival and mitigate apoptotic pathways. These findings have led to a significant amount of research on this molecules potential as a neurotherapeutic. At the forefront of these efforts has been investigation into DADLEs ability to protect neurons and glial cells following ischemia. Additionally, current research is attempting to reveal the dynamic neuroprotective mechanisms that mediate DADLEs therapeutic benefits. This review article discusses the scientific evidence supporting the use of delta opioid family of receptors and ligands as a promising target for therapeutic intervention in neurological disorders, with emphasis on stroke.

Menstrual Blood-Derived Stem Cells: In Vitro and In Vivo Characterization of Functional Effects.

Accumulating evidence has demonstrated that menstrual blood stands as a viable source of stem cells. Menstrual blood-derived stem cells (MenSCs) are morphologically and functionally similar to cells directly extracted from the endometrium, and present dual expression of mesenchymal and embryonic cell markers, thus becoming interesting tools for regenerative medicine. Functional reports show higher proliferative and self-renewal capacities than bone marrow-derived stem cells, as well as successful differentiation into hepatocyte-like cells, glial-like cells, endometrial stroma-like cells, among others. Moreover, menstrual blood stem cells may be used with increased efficiency in reprogramming techniques for induced Pluripotent Stem cell (iPS) generation. Experimental studies have shown successful treatment of stroke, colitis, limb ischemia, coronary disease, Duchennes muscular atrophy and streptozotocin-induced type 1 diabetes animal models with MenSCs. As we envision an off-the-shelf product for cell therapy, cryopreserved MenSCs appear as a feasible clinical product. Clinical applications, although still very limited, have great potential and ongoing studies should be disclosed in the near future.

Current challenges in regenerative medicine for central nervous system disorders

R medicine has propelled to the forefront of innovative treatments for a wide variety of brain illnesses, an emphasis being placed on stem cell-based therapies. Adult stem cells, in particular mesenchymal stem cells (MSCs), are spearheading the cell therapy movement, largely attributed to the growing number of studies confirming their safety, efficacy, and accumulating evidence pointing to stem cells’ multipronged mechanisms of action. Disease indications of regenerative medicine have targeted many neurological disorders, such as stroke, traumatic brain injury (TBI), Huntington’s disease, and peripheral nerve injury.

Harnessing neural stem cells for treating psychiatric symptoms associated with fetal alcohol spectrum disorder and epilepsy

ABSTRACT Brain insults with progressive neurodegeneration are inherent in pathological symptoms that represent many psychiatric illnesses. Neural network disruptions characterized by impaired neurogenesis have been recognized to precede, accompany, and possibly even exacerbate the evolution and progression of symptoms of psychiatric disorders. Here, we focus on the neurodegeneration and the resulting psychiatric symptoms observed in fetal alcohol spectrum disorder and epilepsy, in an effort to show that these two diseases are candidate targets for stem cell therapy. In particular, we provide preclinical evidence in the transplantation of neural stem cells (NSCs) in both conditions, highlighting the potential of this cell‐based treatment for correcting the psychiatric symptoms that plague these two disorders. Additionally, we discuss the challenges of NSC transplantation and offer insights into the mechanisms that may mediate the therapeutic benefits and can be exploited to overcome the hurdles of translating this therapy from the laboratory to the clinic. Our ultimate goal is to advance stem cell therapy for the treatment of psychiatric disorders.

Delta Opioid Receptor and Peptide: A Dynamic Therapy for Stroke and Other Neurological Disorders

Research of the opioid system and its composite receptors and ligands has revealed its promise as a potential therapy for neurodegenerative diseases such as stroke and Parkinsons Disease. In particular, delta opioid receptors (DORs) have been elucidated as a therapeutically distinguished subset of opioid receptors and a compelling target for novel intervention techniques. Research is progressively shedding light on the underlying mechanism of DORs and has revealed two mechanisms of DOR neuroprotection; DORs function to maintain ionic homeostasis and also to trigger endogenous neuroprotective pathways. Delta opioid agonists such as (D-Ala2, D-Leu5) enkephalin (DADLE) have been shown to promote neuronal survival and decrease apoptosis, resulting in a substantial amount of research for its application as a neurological therapeutic. Most notably, DADLE has demonstrated significant potential to reduce cell death following ischemic events. Current research is working to reveal the complex mechanisms of DADLEs neuroprotective properties. Ultimately, our knowledge of the DOR receptors and agonists has made the opioid system a promising target for therapeutic intervention in many neurological disorders.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

An update on intracerebral stem cell grafts

ABSTRACT Introduction: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood–brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.

Advancing stem cells: New therapeutic strategies for treating central nervous system disorders

With stem cells’ ability to initiate regenerative processes in the brain, stem cell transplantation may be a viable method for ameliorating neurological diseases and disorders. Prior research has demonstrated that cell-based therapies heal brain tissue by cell replacement and secretion of neurotrophic factors in various diseases such as ischemic stroke, traumatic brain injury, and Parkinson’s disease (PD). Given the prevalence and severity of these maladies and the promising evidence regarding stem cell transplantation in preclinical animal models, further research and improvements to stem cell therapies are warranted. Moreover, alternative strategies to increase the limited available treatments for these and other brain diseases are welcomed. In this special issue, we explore new methods and knowledge to improve stem cell transplantation in diseases and conditions such as stroke, PD, and depression. Advancing the conventional idea regarding cell replacement in stem cell therapy, stem cells may also transfer healthy mitochondria to diseased ischemic neurons in stroke and improve the therapeutic time window of tissue plasminogen activator (tPA) in a conjunctive therapy for stroke, and human Wharton’s Jelly-derived mesenchymal stromal cells (hWJ-MSCs) may rely mainly on trophic factor secretion to induce neuroprotective effects. In addition, trophic factors such as neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) may enhance stem cell survival and differentiation to dopaminergic neurons for PD treatment, while encapsulating mesenchymal stem cells and GDNF-secreting cells may increase graft survival rates and their ability to promote neurogenesis and neurotrophic factor secretion in therapies for depression and PD. Of note, transfecting stem cells with a contrast agent such as a superparamagnetic iron oxide (SPIO) for tracking with magnetic resonance imaging (MRI) after transplantation may render these transplanted cells more vulnerable to toxicity in ischemic and hypoxic conditions. Moreover, other methods such as transient microglia depletion may protect against cosmic radiation-induced cognitive impairments, and focusing on the collaborative efforts between oligodendrocytes and the neurovascular unit cells to repair damaged white matter may improve therapies for white matter injury. The following ten reviews encompass pertinent investigations regarding regenerative therapies for several central nervous system (CNS) diseases and disorders. Ultimately, this editorial highlights innovative strategies and the current knowledge regarding the utility of stem cells and other cells such as microglia and oligodendrocytes in CNS repair, in the hopes of spawning novel therapies to bolster and increase the insufficient number of effective treatments for the aforementioned diseases and conditions.

Mitochondrial targeting as a novel therapy for stroke

Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit – a communication framework between neurons, their supply microvessels along with glial cells – underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

Growth Factors and Cerebrovascular Diseases

Acute upregulation of growth factors in the brain ensues after onset of cerebrovascular disease, which may indicate a compensatory regenerative process mounted by the injured brain. The increased presence of these therapeutic molecules in the brain under pathologic conditions implicates their key role in modulating brain homeostasis that may involve affording pleiotropic properties, including neurogenic, angiogenic, anti-inflammatory, and antiapoptotic effects. During the progression of these diseases, however, downregulation of growth factors has been detected, indicating the need to replenish these therapeutic molecules as a potential treatment to halt this equally debilitating secondary cell death. We discuss here major growth factors and their beneficial activity in cerebrovascular diseases. Recent developments in emerging technologies for growth factor delivery into the central nervous system are also introduced in this chapter.