Parkinson's disease is characterized by a depletion of dopamine (DA) neurons in the nigrostriatal pathway. Stereotaxic injections of 6- hydroxydopamine (6-OHDA), a selective neurotoxin, into either the medial forebrain bundle or the substantia nigra result in a massive DA denervation of the nigrostriatal pathway. Following unilateral nigrostriatal DA depletion, hemiparkinsonian animals develop a stereotypical rotational behavior when challenged with DA agonists such as apomorphine. The drug-induced rotational behavior has been widely used as the behavioral index of hemiparkinsonian animals, but it has some limitations. Although asymmetries in the rotational behavior may indicate an imbalance of DA contents and release capacity in the bilateral nigrostriatal pathway, the behavior is a pharmacological reaction. Accordingly, the drug-induced rotation test is subject to sensitization effects. The present study proposes the elevated body swing test (EBST) as a measure of asymmetrical motor behavior of hemiparkinsonian animals in a drug-free state. The EBST simply involves elevating the animal by handling its tail and recording the frequency and direction of the swing behavior. Unilateral nigral 6-OHDA-lesioned rats exhibited significant biased swing activity with the direction contralateral to the lesioned side, corresponding to the direction of apomorphine-induced rotations. A 30 sec EBST was noted as the peak time for biased swing activity. At 7 d postlesion (the start of testing), and every week thereafter for a period of 2 months, a fairly stable biased swing activity level was observed. At 1 and 2 months postlesion, the same animals were also challenged with apomorphine.

The long-term consequences of traumatic brain injury (TBI), specifically the detrimental effects of inflammation on the neurogenic niches, are not very well understood. In the present in vivo study, we examined the prolonged pathological outcomes of experimental TBI in different parts of the rat brain with special emphasis on inflammation and neurogenesis. Sixty days after moderate controlled cortical impact injury, adult Sprague-Dawley male rats were euthanized and brain tissues harvested. Antibodies against the activated microglial marker, OX6, the cell cycle-regulating protein marker, Ki67, and the immature neuronal marker, doublecortin, DCX, were used to estimate microglial activation, cell proliferation, and neuronal differentiation, respectively, in the subventricular zone (SVZ), subgranular zone (SGZ), striatum, thalamus, and cerebral peduncle. Stereology-based analyses revealed significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle. In parallel, significant decrements in Ki67-positive proliferating cells in SVZ and SGZ, but only trends of reduced DCX-positive immature neuronal cells in SVZ and SGZ were detected relative to sham control group. These results indicate a progressive deterioration of the TBI brain over time characterized by elevated inflammation and suppressed neurogenesis. Therapeutic intervention at the chronic stage of TBI may confer abrogation of these deleterious cell death processes.

Peripheral nerve injury can lead to great morbidity in those afflicted, ranging from sensory loss, motor loss, chronic pain, or a combination of deficits. Over time, research has investigated neuronal molecular mechanisms implicated in nerve damage, classified nerve injury, and developed surgical techniques for treatment. Despite these advancements, full functional recovery remains less than ideal. In this review, we discuss historical aspects of peripheral nerve injury and introduce nerve transfer as a therapeutic option, as well as an adjunct therapy to transplantation of Schwann cells and their stem cell derivatives for repair of the damaged nerve. This review furthermore, will provide an elaborated discussion on the sources of Schwann cells, including sites to harvest their progenitor and stem cell lines. This reflects the accessibility to an additional, concurrent treatment approach with nerve transfers that, predicated on related research, may increase the efficacy of the current approach. We then discuss the experimental and clinical investigations of both Schwann cells and nerve transfer that are underway. Lastly, we provide the necessary consideration that these two lines of therapeutic approaches should not be exclusive, but conversely, should be pursued as a combined modality given their mutual role in peripheral nerve regeneration.

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The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson’s test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy. Echoing the Stem Cell Therapeutics as an Emerging Paradigm for Stroke and Stroke Treatment Academic Industry Roundtable call for an NIH‐guided collaborative consortium of multiple laboratories in testing the safety and efficacy of stem cells and their derivatives, not just as stand‐alone but preferably in combination with approved thrombolytic or thrombectomy, may further increase the likelihood of successful fruition of translating stem cell therapy for stroke clinical application. The laboratory and clinical experience with MSC therapy for stroke may guide the future translational research on stem cell‐based regenerative medicine in neurological disorders. stem cells translational medicine 2019;8:983&988

Background and Purpose Muse cells are endogenous non-tumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+ cells from the bone marrow (BM) from cultured BM-mesenchymal stem cells (MSCs). After transplantation into neurological disease models, Muse cells exert repair effects, but the exact mechanism remains inconclusive. Methods We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human BM-Muse cells into the peri-lesion brain at two weeks after lacunar infarction in immunodeficient mice. Results Approximately 28% of initially transplanted Muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (~62%), MAP2 (~30%), and GST-pi (~12%). Dextran tracing revealed connections between host neurons and Muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. Conclusions Transplantation at the delayed subacute phase showed Muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.

The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 micromol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 microg/ml or 100 microM) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage.