Conditioned Medium Treatment for the Improvement of Functional Recovery after Spinal Cord Injury: A Meta-Analysis Study.

BACKGROUND: While there is no certain treatment for spinal cord injury (SCI), stem cellbased therapy may be an attractive alternative, but the survival and differentiation of cells in the host tissue are poor. Conditioned medium (CM) has several beneficial effects on cells. OBJECTIVE: In this meta-analysis study, we examined the effect of CM on SCI treatment. METHODS: After searching on MEDLINE, SCOPUS, EMBASE, and Web of Science, first and secondary screening were performed based on title, abstract, and full text. The data were extracted from the included studies, and meta-analysis was performed using STATA.14 software. A standardized mean difference (SMD) with a 95% confidence interval was used to report findings. Quality control and subgroup analysis were also performed. RESULTS: The results from 52 articles and 61 separate experiments showed that CM had a significantly strong effect on improving motor function after SCI (SMD = 2.58; 95% CI: 2.17 to 2.98; p < 0.001) and also analysis of data from 12 articles demonstrated that CM reduced the expression of GFAP marker (SMD = -4.16; p < 0.0001) compared to SCI group without any treatment. Subgroup analysis showed that treatment with CM of neural stem cells was better than CM of mesenchymal stem cells. It was more effective after a mild lesion than a moderate or severe one. The improvement was more pronounced with <4 weeks than >4 weeks follow-up. CONCLUSION: CM had a significant effect in improving motor function after SCI, especially in cases of mild lesions. It has been observed that if CM originates from the neural stem cells, it has a more significant effect than mesenchymal cells.

Treatment with Rapamycin in Animal Models of Traumatic Brain Injuries; a Systematic Review and Meta-Analysis.

Introduction: In light of the potential of enhanced functional and neurological recovery in traumatic brain injury (TBI) with the administration of rapamycin, this systematic review and meta-analysis aimed to investigate the efficacy of rapamycin treatment in animal models of TBI. Methods: An extensive search was conducted in the electronic databases of Medline, Embase, Scopus, and Web of Science by July 1st, 2023. Two independent researchers performed the screening process by reviewing the titles and abstracts and the full texts of the relevant articles, including those meeting the inclusion criteria. Apoptosis rate, inflammation, locomotion, and neurological status were assessed as outcomes. A standardized mean difference (SMD) with a 95% confidence interval (95%CI) was calculated for each experiment, and a pooled effect size was reported. Statistical analyses were performed using STATA 17.0 software. Results: Twelve articles were deemed eligible for inclusion in this meta-analysis. Pooled data analysis indicated notable reductions in the number of apoptotic cells (SMD for Tunnel-positive cells = -1.60; 95%CI: -2.21, -0.99, p<0.001), p-mTOR (SMD=-1.41; 95%CI: -2.03, -0.80, p<0.001), and p-S6 (SMD=-2.27; 95%CI: -3.03, -1.50, p<0.001) in TBI post-treatment. Our analysis also indicated substantial IL-1ß reductions after rapamycin administration (SMD= -1.91; 95%CI: -2.61, -1.21, p<0.001). Moreover, pooled data analysis found significant neurological severity score (NSS) improvements at 24 hours (SMD= -1.16; 95%CI: -1.69, -0.62, p<0.001; I²=0.00%), 72 hours (SMD= -1.44; 95%CI: -2.00, -0.88, p<0.001; I²=0.00%), and 168 hours post-TBI (SMD= -1.56; 95%CI: -2.44, -0.68, p<0.001; I²=63.37%). No such improvement was observed in the grip test. Conclusion: Low to moderate-level evidence demonstrated a significant decrease in apoptotic and inflammatory markers and improved neurological status in rodents with TBI. However, no such improvements were observed in locomotion recovery.

Epinephrine injected into the basolateral amygdala affects anxiety-like behavior and memory performance in stressed rats.

The amygdala is known to mediate in moderating the impacts of emotional arousal and stress on memory. According to a growing body of research, the basolateral amygdala (BLA) is an important locus for integrating neuromodulator influences coordinating the retrieval of different types of memory and anxiety. This study aimed to investigate how the epinephrine in the BLA affects hippocampal fear memory, anxiety, and plasticity in control and stressed rats. For four days, male Wistar rats were exposed to electrical foot-shock stress. Animals received bilateral micro-injections of either vehicle or epinephrine (1 µg/side) into the BLA over four days (5 min before foot-shock stress). Behavioral characteristics (fear memory and anxiety-like behavior), histological features and electrophysiological parameters were investigated. Epinephrine injection into BLA resulted in a considerable impairment of fear memory in stressed rats. On the other hand, epinephrine effectively affected fear memory in control rats. Under stress conditions, epinephrine in the BLA is thought to increase anxiety-like behaviors. Treatment with epinephrine significantly increases the slope of fEPSP in the CA1 region of the hippocampus in the control and stress rats. In different groups, foot-shock stress had no effect on the apical and basal dendritic length in the CA1 region of the hippocampus. These results indicate that activating adrenergic receptors diminish fear memory and anxiety-like behaviors in the foot-shock stress, which this impact is independent of CA1 long-term potentiation induction.

Could conditioned medium be used instead of stem cell transplantation to repair spinal cord injury in animal models? Identifying knowledge gaps.

The drawbacks of stem cell (SC) therapies have led to investigations of SC conditioned medium (CM) instead of SC transplantation in the repair of spinal cord injury (SCI). However, the effectiveness of CM in comparison with cell transplantation in SCI models remain an open and intriguing question. The focus of this review was to survey existing publications addressing this comparison. The review included articles from electronic databases Medline, Embase, Scopus, and Web of Science that included comparisons of the effects of CM versus SC transplantation and versus controls on locomotion after SCI. The search yielded 5 studies and 6 experiments. The results indicated that there was insufficient evidence to conclude that treatment with CM and source cells were equally effective (SMD = 0.12; 95% CI = -0.36 to 0.59; p = 0.07). Regarding investigations of separate effects of SCs versus CM, there currently is limited evidence on efficacy in SCI models. This highlights a notable concern affecting this field. Thus, we identified critical knowledge gaps concerning comparisons of the efficacy of therapeutic application of SC and their derived CM on functional recovery following SCI.

Alterations in the intrinsic discharge activity of CA1 pyramidal neurons associated with possible changes in the NADPH diaphorase activity in a rat model of autism induced by prenatal exposure to valproic acid.

Autism spectrum disorder is a neurodevelopmental disorder characterized by sensory abnormalities, social skills impairment and cognitive deficits. Although recent evidence indicated that induction of autism-like behavior in animal models causes abnormal neuronal excitability, the impact of autism on neuronal properties is still an important issue. Thus, new findings at the cellular level may shed light on the pathophysiology of autism and may help to find effective treatment strategies. Here, we investigated the behavioral, electrophysiological and histochemical impacts of prenatal exposure to valproic acid (VPA) in rats. Findings revealed that VPA exposure caused a significant increase in the hot plate response latency. The novel object recognition ability was also impaired in VPA-exposed rats. Along with these behavioral alterations, neurons from VPA-exposed animals exhibited altered excitability features in response to depolarizing current injections relative to control neurons. In the VPA-exposed group, these changes consisted of a significant increase in the amplitude, evoked firing frequency and the steady-state standard deviation of spike timing of action potentials (APs). Moreover, the half-width, the AHP amplitude and the decay time constant of APs were significantly decreased in this group. These changes in the evoked electrophysiological properties were accompanied by intrinsic hyperexcitability and lower spike-frequency adaptation and also a significant increase in the number of NADPH-diaphorase stained neurons in the hippocampal CA1 area of the VPA-exposed rats. Taken together, findings demonstrate that abnormal nociception and recognition memory is associated with alterations in the neuronal responsiveness and nitrergic system in a rat model of autism-like.

5-HT7 receptor activation rescues impaired synaptic plasticity in an autistic-like rat model induced by prenatal VPA exposure.

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.

Enhancement of intrinsic neuronal excitability-mediated by a reduction in hyperpolarization-activated cation current (Ih ) in hippocampal CA1 neurons in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) is associated with epileptiform activity in the hippocampus; however, the underlying mechanisms have not been fully determined. The goal was to understand what changes take place in intrinsic neuronal physiology in the hippocampus after blunt force trauma to the cortex. In this context, hyperpolarization-activated cation current (Ih ) currents may have a critical role in modulating the neuronal intrinsic membrane excitability; therefore, its contribution to the TBI-induced hyperexcitability was assessed. In a model of TBI caused by controlled cortical impact (CCI), the intrinsic electrophysiological properties of pyramidal neurons were examined 1 week after TBI induction in rats. Whole-cell patch-clamp recordings were performed under current- and voltage-clamp conditions following ionotropic receptors blockade. Induction of TBI caused changes in the intrinsic excitability of pyramidal neurons, as shown by a significant increase and decrease in firing frequency and in the rheobase current, respectively (p < .05). The evoked firing rate and the action potential time to peak were also significantly increased and decreased, respectively (p < .05). In the TBI group, the amplitude of instantaneous and steady-state Ih currents was both significantly smaller than those in the control group (p < .05). The Ih current density was also significantly decreased (p < .001). Findings indicated that TBI led to an increase in the intrinsic excitability in CA1 pyramidal neurons and changes in Ih current could be, in part, one of the underlying mechanisms involved in this hyperexcitability.

Hyperexcitability of hippocampal CA1 pyramidal neurons in male offspring of a rat model of autism spectrum disorder (ASD) induced by prenatal exposure to valproic acid: A possible involvement of Ih channel current.

Autism spectrum disorder (ASD) is a common neuropsychiatric disorder, which is characterized by impairment in social interaction and cognitive behaviors. However, there is not much electrophysiological data available on alterations of neuronal excitability in autism. Here, we assessed the pattern of neuronal excitability and the possible contribution of Ih current to the altered excitability of hippocampal CA1 pyramidal neurons in a rat model of VPA-induced ASD-like behavior. Pregnant Wistar rats received valproic acid (VPA, 500 mg/kg) at gestational day 12.5. All offspring were subjected to behavioral tests to verify the induction of ASD-like behaviors. On postnatal day (PND) 45, whole-cell patch-clamp recordings were performed on hippocampal CA1 pyramidal neurons in slices obtained from control and prenatal VPA-exposed pups, under current and voltage-clamp conditions. Our results showed that beside the induction of behavioral abnormalities in ASD pups, higher excitability of hippocampal CA1 pyramidal neurons was also prominent, as evidenced by a significant increase in the spontaneous firing frequency and evoked firing rate, as well as a significant decrease in the rheobase current. In the VPA-exposed group, the steady-state (ISS) Ih current amplitude was significantly smaller than control cells. The Ih half-activation voltage shifted toward more negative potentials in the VPA-exposed group. The sag ratio was also significantly less than the control cells. Moreover, the cell soma size was shifted toward smaller diameter in VPA-exposed group. Overall, induction of ASD-like behaviors was associated with neuronal hyperexcitability, which, at least in part, could be attributed to the changes in Ih channels function.

The protective effect of hydrogen sulfide (H2S) on traumatic brain injury (TBI) induced memory deficits in rats.

Traumatic brain injury (TBI), as an expanding public health epidemic, is a common cause of death among youth. TBI is associated with cognitive deficits and memory impairment. Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. In the present study the potential neuroprotective role of sodium hydrosulfide (NaHS), an H2S donor on TBI induced memory deficit in a rat model of controlled cortical impact (CCI) injury was investigated. CCI model was used to induce TBI. Male rats were randomly assigned into the following groups: control, sham, sham treated with NaHS, TBI, and TBI treated with NaHS (3 and 5mg/kg). NaHS was injected intraperitoneally 5min before TBI induction. Learning and memory were assessed using Morris water maze (MWM) on days 8-12 following injury. CCI resulted in MWM deficits. Injured animals showed a slower rate of acquisition with respect to the sham-operated animals [F (1, 24)=13.97, P<0.01, two-way ANOVA]. NaHS improved spatial memory impairment of injured rats. Treatment with NaHS (5 mg/kg) decreased the escape latency [F (1, 24)=7.559, P<0.05, two-way ANOVA] and traveled distance [F (1, 12)=6.398, P<0.05, Two way ANOVA)]. In probe test, injured animals spent less time in target zone (P<0.05, unpaired t-test) and NaHS did not have any effect on this parameter (p>0.05, one way ANOVA). These findings suggest that NaHS has a neuroprotective effect on TBI-induced memory impairment in rats.

Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats.

Although it is well established that chronic stress impairs spatial learning and memory, few studies have investigated possible ways to prevent its deleterious effects. Here, we investigated the effects of Crocus sativus L., commonly known as saffron, and its active constituent crocin on learning and memory loss and the induction of oxidative stress in the hippocampus by chronic stress. Rats were injected with saffron extract, crocin or vehicle over a period of 21 days while being exposed to chronic restraint stress (6 h/day). After this, they were trained and tested on a water-maze spatial memory task. They performed four trials per day for 5 consecutive days, and this was followed by a probe trial two days later. At the end of the behavioral testing, several parameters of oxidative stress in the hippocampus were measured. Treatment with saffron extract or crocin blocked the ability of chronic stress to impair spatial learning and memory retention. Relative to controls that received vehicle, stressed animals that received saffron extract or crocin had significantly higher levels of lipid peroxidation products, significantly higher activities of antioxidant enzymes including glutathione peroxidase, glutathione reductase and superoxide dismutase and significantly lower total antioxidant reactivity capacity. Finally, crocin significantly decreased plasma levels of corticosterone, as measured after the end of stress. These observations indicate that saffron and its active constituent crocin can prevent the impairment of learning and memory as well as the oxidative stress damage to the hippocampus induced by chronic stress. Thus, using these substances may be useful in pharmacological alleviation of cognitive deficits.

The glucocorticoid system is required for the voluntary exercise-induced enhancement of learning and memory in rats.

Although it is well established that voluntary exercise can improve cognitive functions, the underlying mechanisms are largely unknown. Glucocorticoids play an important role in learning and memory functions. This study addressed whether the glucocorticoid system would play a role in the exercise-induced enhancement of learning and memory. Intact rats or those that were either adrenalectomized or daily given the corticosterone-synthesis inhibitor metyrapone were allowed to freely exercise in a running wheel for 10 days. Control animals were kept sedentary for this period. After this period, they were trained and tested on a water-maze spatial task using three-trial per day for 5 consecutive days, succeeded by a probe trial two days later. Exercise increased plasma corticosterone levels, as assessed after this 10-day period. Both adrenalectomy and metyrapone slightly reduced running-wheel activity. Adrenalectomy reduced the plasma corticosterone levels to almost zero whereas metyrapone selectively blocked the exercise-induced increase in corticosterone levels. Exercise significantly improved performance during both training and retention of the water-maze task whereas this effect was absent in both adrenalectomized and metyrapone-treated rats. These findings indicate that the glucocorticoid system play a crucial role in the beneficial effects of voluntary exercise on cognitive functions in rats.