Design and synthesis of nano-biomaterials based on graphene and local delivery of cerebrolysin into the injured spinal cord of mice, promising neural restoration.

Spinal cord injury (SCI) is an incurable and catastrophic health issue with no clinical solution. As part of cascade reactions, the inflammatory process and fibrous glial scar production aggravate the amount of lesion through a secondary damage mechanism, encouraging scientists from other disciplines to investigate new paths for solving this problem. Graphene oxide (GO) and its derivatives are among the most promising biomedical and nerve tissue regeneration materials due to their remarkable chemical, mechanical, and electrical properties. This paper designs and introduces a new GO-based nanomaterial to minimize inflammation and stimulate neurite regrowth. To improve biocompatibility, biodegradability, and cell proliferation, GO plates were modified with polyethylene glycol (PEG) and Au nanoparticles as neuroprotective and antibacterial agents, respectively. Preliminary biological investigations on bone marrow derived mesenchymal stem cells (BM-MSCs) with various concentrations of a graphenic nanocarrier indicated a lack of cell toxicity and an enhancement in BM-MSC proliferation of about 10% after 48 hours. Therapeutic nanostructures were used in the T10 segment of a mouse SCI model. The pathological and immunohistochemical data revealed that refilling tissue cavities, decreasing degeneration, and establishing neuroregeneration resulted in a considerable improvement of hind limb motor function. Furthermore, compared to the nanocomposite mixture alone, the intraspinal delivery of cerebrolysin (CRL) had a more satisfying impact on nerve regrowth, cystic cavity, hemorrhage avoidance, and motor function enhancement. This study demonstrates the potential of graphenic nanomaterials for SCI treatment and neuroregeneration applications.

Aging and age-related diseases with a focus on therapeutic potentials of young blood/plasma.

Aging is accompanied by alterations in the body with time-related to decline of physiological integrity and functionality process, responsible for increasing diseases and vulnerability to death. Several ages associated with biomarkers were observed in red blood cells, and consequently plasma proteins have a critical rejuvenating role in the aging process and age-related disorders. Advanced age is a risk factor for a broad spectrum of diseases and disorders such as cardiovascular diseases, musculoskeletal disorders and liver, chronic kidney disease, neurodegenerative diseases, and cancer because of loss of regenerative capacity, correlated to reduced systemic factors and raise of pro-inflammatory cytokines. Most studies have shown that systemic factors in young blood/plasma can strongly protect against age-related diseases in various tissues by restoring autophagy, increasing neurogenesis, and reducing oxidative stress, inflammation, and apoptosis. Here, we focus on the current advances in using young plasma or blood to combat aging and age-related diseases and summarize the experimental and clinical evidence supporting this approach. Based on reports, young plasma or blood is new a therapeutic approach to aging and age-associated diseases.

Chronic Sustained Hypoxia Leads to Brainstem Tauopathy and Declines the Power of Rhythms in the Ventrolateral Medulla: Shedding Light on a Possible Mechanism.

Hypoxia, especially the chronic type, leads to disruptive results in the brain that may contribute to the pathogenesis of some neurodegenerative diseases such as Alzheimer's disease (AD). The ventrolateral medulla (VLM) contains clusters of interneurons, such as the pre-Bötzinger complex (preBötC), that generate the main respiratory rhythm drive. We hypothesized that exposing animals to chronic sustained hypoxia (CSH) might develop tauopathy in the brainstem, consequently changing the rhythmic manifestations of respiratory neurons. In this study, old (20-22 months) and young (2-3 months) male rats were subjected to CSH (10 ± 0.5% O2) for ten consecutive days. Western blotting and immunofluorescence (IF) staining were used to evaluate phosphorylated tau. Mitochondrial membrane potential (MMP or ∆ψm) and reactive oxygen species (ROS) production were measured to assess mitochondrial function. In vivo diaphragm's electromyography (dEMG) and local field potential (LFP) recordings from preBötC were employed to assess the respiratory factors and rhythmic representation of preBötC, respectively. Findings showed that ROS production increased significantly in hypoxic groups, associated with a significant decline in ∆ψm. In addition, tau phosphorylation elevated in the brainstem of hypoxic groups. On the other hand, the power of rhythms declined significantly in the preBötC of hypoxic rats, parallel with changes in the respiratory rate, total respiration time, and expiration time. Moreover, there was a positive and statistically significant correlation between LFP rhythm's power and inspiration time. Our data showed that besides CSH, aging also contributed to mitochondrial dysfunction, tau hyperphosphorylation, LFP rhythms' power decline, and changes in respiratory factors.

The Impact of Cerebral Ischemia on Antioxidant Enzymes Activity and Neuronal Damage in the Hippocampus.

Cerebral ischemia and subsequent reperfusion, leading to reduced blood supply to specific brain areas, remain significant contributors to neurological damage, disability, and mortality. Among the vulnerable regions, the subcortical areas, including the hippocampus, are particularly susceptible to ischemia-induced injuries, with the extent of damage influenced by the different stages of ischemia. Neural tissue undergoes various changes and damage due to intricate biochemical reactions involving free radicals, oxidative stress, inflammatory responses, and glutamate toxicity. The consequences of these processes can result in irreversible harm. Notably, free radicals play a pivotal role in the neuropathological mechanisms following ischemia, contributing to oxidative stress. Therefore, the function of antioxidant enzymes after ischemia becomes crucial in preventing hippocampal damage caused by oxidative stress. This study explores hippocampal neuronal damage and enzymatic antioxidant activity during ischemia and reperfusion's early and late stages.

Spinal cord injury leads to more neurodegeneration in the hippocampus of aged male rats compared to young rats.

Although the disruptive effects of spinal cord injury (SCI) on the hippocampus have been confirmed in some animal studies, no study has investigated its retrograde manifestations in the hippocampus of aged subjects. Herein, we compared the aged rats with young ones 3 weeks after the induction of SCI (Groups: Sham.Young, SCI.Young, Sham.Aged, SCI.Aged). The locomotion, hippocampal apoptosis, hippocampal rhythms (Delta, Theta, Beta, Gamma) max frequency (Max.rf) and power, hippocampal neurogenesis, and hippocampal receptors (NMDA, GABA A, Muscarinic1/M1), which are important in the generation of rhythms and neurogenesis, were compared in aged rats in contrast to young rats. At the end of the third week, the number of apoptotic (Tunel+) cells in the hippocampus (CA1, DG) of SCI animals was significantly higher compared to the sham animals, and also, it was significantly higher in the SCI.Aged group compared to SCI.Young group. Moreover, the rate of neurogenesis (DCX+, BrdU+ cells) and expression of M1 and NMDA receptors were significantly lower in the SCI.Aged group compared to SCI.Young group. The power and Max.fr of all rhythms were significantly lower in SCI groups compared to sham groups. Despite the decrease in the power of rhythms in the SCI.Aged group compared to SCI.Young group, there was no significant difference between them, and in terms of Max.fr index, only the Max.fr of theta and beta rhythms were significantly lower in the SCI.Aged group compared to SCI.Young group. This study showed that SCI could cause more neurodegeneration in the hippocampus of aged animals compared to young animals.

Intersection of hippocampus and spinal cord: a focus on the hippocampal alpha-synuclein accumulation, dopaminergic receptors, neurogenesis, and cognitive function following spinal cord injury in male rats.

BACKGROUND: Following Spinal Cord Injury (SCI), innumerable inflammatory and degenerative fluctuations appear in the injured site, and even remotely in manifold areas of the brain. Howbeit, inflammatory, degenerative, and oscillatory changes of motor cortices have been demonstrated to be due to SCI, according to recent studies confirming the involvement of cognitive areas of the brain, such as hippocampus and prefrontal cortex. Therefore, addressing SCI induced cognitive complications via different sights can be contributory in the treatment approaches. RESULTS: Herein, we used 16 male Wistar rats (Sham = 8, SCI = 8). Immunohistochemical results revealed that spinal cord contusion significantly increases the accumulation of alpha-synuclein and decreases the expression of Doublecortin (DCX) in the hippocampal regions like Cornu Ammonis1 (CA1) and Dentate Gyrus (DG). Theses degenerative manifestations were parallel with a low expression of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), SRY (sex determining region Y)-box 2 (SOX2), and dopaminergic receptors (D1 and D5). Additionally, based on the TUNEL assay analysis, SCI significantly increased the number of apoptotic cells in the CA1 and DG regions. Cognitive function of the animals was assessed, using the O-X maze and Novel Object Recognition (NORT); the obtained findings indicted that after SCI, hippocampal neurodegeneration significantly coincides with the impairment of learning, memory and recognition capability of the injured animals. CONCLUSIONS: Based on the obtained findings, herein SCI reduces neurogenesis, decreases the expression of D1 and D5, and increases apoptosis in the hippocampus, which are all associated with cognitive function deficits.

Spinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela.

Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI's pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients. SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.

Forelimb Motor Skills Deficits Following Thoracic Spinal Cord Injury: Underlying Dopaminergic and Neural Oscillatory Changes in Rat Primary Motor Cortex.

The loss of spinal sensorimotor pathways following spinal cord injury (SCI) can induce retrograde neurodegeneration in the primary motor cortex (M1). However, the effect of thoracic SCI on forelimb motor skills has not been studied clearly. So, herein we aimed to examine the effects of the thoracic SCI model on forelimb motor skills learning, parallel with dopaminergic and oscillatory changes in hindlimb and forelimb areas (HLA and FLA) of M1 in rats. Male Wistar rats were randomly subjected to laminectomy (Control) or contusion SCI at the thoracic (T10) level. Oscillatory activity and motor skills performance were evaluated for six consecutive days using local field potential (LFP) recording and skilled forelimb reaching task, respectively. Dopamine (DA) levels and expression of dopamine receptors (D1R and D2R) were determined in HLA and FLA by ELISA and western blotting. LFP recording results showed a sustained increase of LFP power in SCI rats compared with uninjured rats through skilled reaching training. Also, the SCI group had a lower reaching performance and learning rate in contrast to the Control group. Biochemical analysis of HLA and FLA showed a reduction in DA levels and expression of D1R and D2R after SCI. According to these findings, thoracic SCI causes aberrant changes in the oscillatory activity and dopaminergic system of M1, which are not restricted to HLA but also found in FLA accompanied by a deficit in forelimb motor skills performance.Summary statement: The reorganization of the primary motor cortex, following spinal cord injury, is not restricted to the hind limb area, and interestingly extends to the forelimb limb area, which appears as a dysfunctional change in oscillations and dopaminergic system, associated with a deficit in motor skills learning of forelimb.