Human Mesenchymal Stem Cell Transplantation Improved Functional Outcomes Following Spinal Cord Injury Concomitantly with Neuroblast Regeneration.

Purpose: Spinal cord injury (SCI) is damage to the spinal cord that resulted in irreversible neuronal loss, glial scar formation and axonal injury. Herein, we used the human amniotic fluid mesenchymal stem cells (hAF-MSCs) and their conditioned medium (CM), to investigate their ability in neuroblast and astrocyte production as well as functional recovery following SCI. Methods: Fifty-four adult rats were randomly divided into nine groups (n=6), included: Control, SCI, (SCI + DMEM), (SCI + CM), (SCI + MSCs), (SCI + Astrocyte), (SCI + Astrocyte + DMEM), (SCI + Astrocyte + CM) and (SCI + Astrocyte + MSCs). Following laminectomy and SCI induction, DMEM, CM, MSCs, and astrocytes were injected. Western blot was performed to explore the levels of the Sox2 protein in the MSCs-CM. The immunofluorescence staining against doublecortin (DCX) and glial fibrillary acidic protein (GFAP) was done. Finally, Basso-Beattie-Brenham (BBB) locomotor test was conducted to assess the neurological outcomes. Results: Our results showed that the MSCs increased the number of endogenous DCX-positive cells and decreased the number of GFAP-positive cells by mediating juxtacrine and paracrine mechanisms (P<0.001). Transplanted human astrocytes were converted to neuroblasts rather than astrocytes under influence of MSCs and CM in the SCI. Moreover, functional recovery indexes were promoted in those groups that received MSCs and CM. Conclusion: Taken together, our data indicate the MSCs via juxtacrine and paracrine pathways could direct the spinal cord endogenous neural stem cells (NSCs) to the neuroblasts lineage which indicates the capability of the MSCs in the increasing of the number of DCX-positive cells and astrocytes decline.

Cerebral dopamine neurotrophic factor increases proliferation, Migration and differentiation of subventricular zone neuroblasts in photothrombotic stroke model of mouse.

BACKGROUND: Cerebral ischemic stroke can induce the proliferation of subventricular zone (SVZ) neural stem cells (NSCs) in the adult brain. However, this reparative process is restricted because of NSCs' death shortly after injury or disability of them to reach the infarct boundary. In the present study, we investigated the ability of cerebral dopamine neurotrophic factor (CDNF) on the attraction of SVZ-resident NSCs toward the lesioned area and neurological recovery in a photothrombotic (PT) stroke model of mice METHODS: The mice were assigned to three groups stroke, stroke+phosphate buffered saline (PBS), and stroke+CDNF. Migration of SVZ NSCs were evaluated by BrdU/doublecortin (DCX) double immunofluorescence method on days 7 and 14 and their differentiation were evaluated by BrdU/ Neuronal Nuclei (NeuN) double immunofluorescence method 28 days after intra-SVZ CDNF injection. Serial coronal sections were stained with cresyl violet to detect the infarct volume and a modified neurological severity score (mNSS) was performed to assess the neurological performance RESULTS: Injection of CDNF increased the proliferation of SVZ NSCs and the number of DCX-expressing neuroblasts migrated from the SVZ toward the ischemic site. It also enhanced the differentiation of migrated neuroblasts into the mature neurons in the lesioned site. Along with this, the infarct volume was significantly decreased and the neurological performance was improved as compared to other groups CONCLUSION: These results demonstrate that CDNF is capable of enhancing the proliferation of NSCs residing in the SVZ and their migration toward the ischemia region and finally, differentiation of them in stroke mice, concomitantly decreased infarct volume and improved neurological abilities were revealed.

Hippocampal neurodegeneration and rhythms mirror each other during acute spinal cord injury in male rats.

Spinal Cord Injury (SCI), triggers neurodegenerative changes in the spinal cord, and simultaneously alters oscillatory manifestations of motor cortex. However, these disturbances may not be limited to motor areas and other parts such as hippocampus, which is vital in the neurogenesis and cognitive function, may be affected in the neurogenic and oscillatory manners. Addressing this remarkable complication of SCI, we evaluated the hippocampal neurogenesis and rhythms through acute phase of SCI. In the present study, we used 40 male rats (Sham.W1 = 10, SCI.W1 = 10, Sham.W2 = 10, SCI.W2 = 10), and findings revealed that contusive SCI declines hippocampal rhythms (Delta, Theta, Beta, Gamma) power and max-frequency. Also, there was a significant decrease in the DCX + and BrdU + cells of the dentate gyrus; correlated significantly with rhythms power decline. Considering the TUNEL assay analysis, there were significantly greater apoptotic cells, in the CA1, CA3, and DG regions of injured animals. Furthermore, according to the western blotting analysis, the expression of receptors (NMDA, GABAA, Muscarinic1), which are essential in the neurogenesis and generation of rhythms significantly attenuated following SCI. Our study demonstrated that acute SCI, alters the power and max-frequency of hippocampal rhythms parallel with changes in the hippocampal neurogenesis, apoptosis, and receptors expression.

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View.

There is increasing evidence of neurological manifestations and complications in patients with coronavirus disease 19 (COVID-19). More than one-quarter of patients with COVID-19 developed various neurological symptoms, ranging from headache and dizziness to more serious medical conditions, such as seizures and stroke. The recent investigations introduced hyposmia as a potential early criterion of infection with COVID-19. Despite the high mortality and morbidity rate of COVID-19, its exact mechanism of action and pathogenesis is not well characterized. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could interact with angiotensin-converting enzyme 2 (ACE2) in the endothelial, neural, and glial cells. In the present study, we reviewed the most common neurological manifestations and complications that emerged after infection with the SARS-CoV-2 and discussed their possible relation to the expression and function of ACE2. Comprehensive and detailed studies are required to uncover how this virus invades the neural system as well as other critical organs.

A potential entanglement between the spinal cord and hippocampus: Theta rhythm correlates with neurogenesis deficiency following spinal cord injury in male rats.

Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus-dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI-induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y-maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.

Prefrontal dopaminergic system and its role in working memory and cognition in spinal cord-injured rats.

NEW FINDINGS: What is the central question of this study? How does spinal cord injury affect prefrontal cortex function and the expression of dopamine receptors? What is the main finding and its importance? Spinal cord injury impaired cognitive function, which was associated with reduced dopamine receptor expression in the prefrontal cortex. ABSTRACT: The effect of spinal cord injury (SCI) has been studied widely in paraplegia and motor areas of the brain, but its mechanisms in memory and cognitive impairment remain controversial. Here, we focused on the impact of SCI on prefrontal performance via dopamine levels and receptors. We divided 18 male rats into three groups, i.e. control, laminectomy and SCI groups. Laminectomy and SCI were induced at T10 of the spinal cord. One week later, after locomotor recovery, the novel object recognition and T-maze (spontaneous alternation) tests were applied. After behavioural assessments, the rats were killed and their brain tissues harvested. According to the behavioural findings, cognitive function was impaired in the SCI group (P < 0.05). Also, SCI significantly increased the dopamine level and decreased the expression of dopamine receptors in the prefrontal cortex 2 weeks after injury (P < 0.05). Given the role of dopamine in cognition, SCI could impair novel object recognition and spatial working memory via dopaminergic systems.

Impacts of epidural electrical stimulation on Wnt signaling, FAAH, and BDNF following thoracic spinal cord injury in rat.

Electrical stimulation (ES) has been shown to improve some of impairments after spinal cord injury (SCI), but the underlying mechanisms remain unclear. The Wnt signaling pathways and the endocannabinoid system appear to be modulated in response to SCI. This study aimed to investigate the effect of ES therapy on the activity of canonical/noncanonical Wnt signaling pathways, brain-derived neurotrophic factor (BDNF), and fatty-acid amide hydrolase (FAAH), which regulate endocannabinoids levels. Forty male Wistar rats were randomly divided into four groups: (a) Sham, (b) laminectomy + epidural subthreshold ES, (c) SCI, and (d) SCI + epidural subthreshold ES. A moderate contusion SCI was performed at the thoracic level (T10). Epidural subthreshold ES was delivered to upper the level of T10 segment every day (1 hr/rat) for 2 weeks. Then, animals were killed and immunoblotting was used to assess spinal cord parameters. Results revealed that ES intervention for 14 days could significantly increase wingless-type3 (Wnt3), Wnt7, ß-catenin, Nestin, and cyclin D1 levels, as well as phosphorylation of glycogen synthase kinase 3ß and Jun N-terminal kinase. Additionally, SCI reduced BDNF and FAAH levels, and ES increased BDNF and FAAH levels in the injury site. We propose that ES therapy may improve some of impairments after SCI through Wnt signaling pathways. Outcomes also suggest that BDNF and FAAH are important players in the beneficial impacts of ES therapy. However, the precise mechanism of BDNF, FAAH, and Wnt signaling pathways on SCI requires further investigation.

Theta Oscillations Through Hippocampal/Prefrontal Pathway: Importance in Cognitive Performances.

Among various hippocampal rhythms, including sharp-wave ripples, gamma, and theta, theta rhythm is crucial for cognitive processing, particularly learning and memory. Theta oscillations are observable in both humans and rodents during spatial navigations. However, the hippocampus (Hip) is well known as the generator of current rhythm, and other brain areas, such as prefrontal cortex (PFC), can be affected by theta rhythm, too. The PFC is a core structure for the execution of diverse higher cortical functions defined as cognition. This region is connected to the hippocampus through the hippocampal/prefrontal pathway; hereby, theta oscillations convey hippocampal inputs to the PFC and simultaneously synchronize the activity of these two regions during memory, learning and other cognitive tasks. Importantly, thalamic nucleus reunions (nRE) and basolateral amygdala are salient relay structures modulating the synchronization, firing rate, and phase-locking of the hippocampal/prefrontal oscillations. Herein, we summarized experimental studies, chiefly animal researches in which the theta rhythm of the Hip-PFC axis was investigated using either electrophysiological assessments in rodent or integrated diffusion-weighted imaging and electroencephalography in human cases under memory-based tasks. Moreover, we briefly reviewed alterations of theta rhythm in some CNS diseases with the main feature of cognitive disturbance. Interestingly, animal studies implied the interruption of theta synchronization in psychiatric disorders such as schizophrenia and depression. To disclose the precise role of theta rhythm fluctuations through the Hip-PFC axis in cognitive performances, further studies are needed.

Neuroprotective effect of ghrelin in methamphetamine-treated male rats.

This study aimed to investigate the effects of ghrelin, as a neuroprotective agent, on cognitive impairment and apoptosis pathway in methamphetamine-treated male rats. Sixty adult male Wistar rats were randomly divided into six groups (n = 10): Saline/Saline (SS), Saline/Ghrelin (SG), Methamphetamine/Simultaneous Saline (MSS), Methamphetamine/Simultaneous Ghrelin (MSG), Methamphetamine/Delayed Saline (MDS), and Methamphetamine/Delayed ghrelin (MDG). Methamphetamine (5 mg/kg) and ghrelin (5 nM/kg) were injected intraperitoneally. Spatial and passive avoidance memories were evaluated by Morris water maze (MWM) and Shuttle box, respectively. Hippocampal expression levels of Cytochrome-C, Caspase 3, and Bax/Bcl-2 ratio were evaluated by Western blotting. TUNEL assay was performed to detect hippocampal neuronal apoptosis. Our results showed that time spent in the target quadrant in MSS group was less than the control group. However, simultaneous ghrelin treatment could increase it. Ghrelin treatment reversed methamphetamine effects on hippocampal protein expression of Caspase 3 and Cytochrome-C, and BAX/Bcl-2 ratio. TUNEL assay showed an increase in the number of apoptotic cells in methamphetamine-treated animals, while ghrelin treatment decreased apoptosis. These results indicate that ghrelin treatment could improve spatial memory and reduce neuronal apoptosis in the hippocampus of methamphetamine-treated animals.