Horn Of Spinal Cord Research Articles

Factors modifying the course of spinal muscular atrophy 5q

Proximal spinal muscular atrophy 5q (SMA 5q) is a severe autosomal recessive neuromuscular disease characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons of the anterior horns of the spinal cord. To date, the main modifying factor of spinal muscular atrophy is considered to be the number of copies of the SMN2 gene. However, a sufficient number of other genetic and non-genetic modifiers of the course of SMA have been described.Advanced neonatal screening, which started in the Russian Federation in 2023, allows detecting SMA 5q before the onset of clinical manifestations. However, to start therapy and select the right drug, it is important to know not only the main modifying factor (the number of copies of SMN2), but also other genetic causes that may affect the age of the disease manifestation or the effectiveness of therapy.

Unveiling the natural history of paralysis in metastatic cervical spinal tumor: An experimental study

IntroductionDespite the relatively low prevalence of metastatic cervical spinal tumor, these entities give rise to more profound complications than thoracic and lumbar spinal tumor. However, it is regrettable that experimental investigation has thus far shown a dearth of attention to metastatic cervical spinal tumor. Research questionWhat is the conceptualization and realization of quadriparesis resulting from metastatic cervical spinal tumor? Material and methodsUsing Fischer 344 rats as the experimental cohort, this study orchestrated the engraftment of tumor cells procured from the 13762 MAT B III cell line (RRID: CVCL_3475), which represents mammary adenocarcinoma. These cells were engrafted into the vertebrae of the cervical spine. A comprehensive inquiry encompassing behavioral assessments, histological evaluations, and microangiographic analyses conducted after the aforementioned cellular transplantation was subsequently pursued. ResultsThe incidence of cervical paralysis was 61.1%. Notably, the evolution of paralysis was unfurled by two distinctive temporal phases within its natural history. A meticulous histological examination facilitated delineation of the tumor's posterior expansion within the spinal canal. Simultaneously, the tumor exhibited anterior and lateral encroachment on the spinal cord, inducing compression from all sides. Augmented by microangiographic investigations, conspicuous attenuation of stained blood vessels within the affected anterior horn and funiculus of the spinal cord was observed. Discussion and conclusionThe pathological advancement of paralysis stemming from metastatic cervical spinal tumor is now apprehended to unfurl through a biphasic phase. The initial phase is characterized by gradual unfurling spanning several days, juxtaposed against the second phase marked by swift and accelerated progression.

Disseminated ependymal dysembryoplastic neuroepithelial tumor: a case report and literature review

We present a rare case of T1- and T2-negative ventricular system tumor. Only FIESTA imaging revealed dissemination with multiple focal lesions of the third ventricle, its bottom and lateral walls, anterior horns of lateral ventricles, cerebellar vermis, cervical and lumbar spinal cord. The patient underwent transcortical endoscopic biopsy of the third ventricle tumor with simultaneous ventriculoperitoneal shunting. DNET was diagnosed, and radiotherapy was subsequently performed. Literature data on this issue were analyzed. To date, disseminated forms of DNET are extremely rare. X-ray features and morphological results allow us to establish the correct diagnosis and determine further treatment strategy.

Protectin D1 ameliorates non-compressive lumbar disc herniation through SIRT1-mediated CGRP signaling.

Background. Neuro-inflammatory response promotes the initiation and sustenance of lumbar disc herniation (LDH). Protectin D1 (PD1), as a new type of specialized pro-resolving mediator (SPM), can improve the prognosis of various inflammatory diseases. Recent studies have shown that over representation of calcitonin gene-related peptides (CGRP) may activate nociceptive signaling following nerve injury. Silent information regulator 1 (SIRT1) is ubiquitously expressed in the dorsal horn of the spinal cord and plays a role in the pathogenesis of LDH. In this study, we investigated the analgesic effects of PD1 and elucidated the impact of neurogenic inflammation in the pathogenesis of neuropathic pain induced by non-compressive lumbar disc herniation (NCLDH) in a rat model. Methods. NCLDH models were established by applying protruding autologous nucleus pulposus to the L5 Dorsal root ganglion (DRG). PD1, SIRT1 antagonist or agonist, CGRP or antagonist were administered as daily intrathecal injections for three consecutive days postoperatively. Behavioral tests were conducted to assess mechanical and thermal hyperalgesia. The ipsilateral lumbar (L4-6) segment of the spinal dorsal horn was isolated for further analysis. Alterations in the release of SIRT1 and CGRP were explored using western blot and immunofluorescence. Results. Application of protruded nucleus (NP) materials to the DRG induced mechanical and thermal allodynia symptoms, and deregulated the expression of pro-inflammatory and anti-inflammatory cytokines in rats. Intrathecal delivery of PD1 significantly reversed the NCLDH-induced imbalance in neuro-inflammatory response and alleviated the symptoms of mechanical and thermal hyperalgesia. In addition, NP application to the DGRs resulted the spinal upregulation of CGRP and SIRT1 expression, which was almost restored by intrathecal injection of PD1 in a dose-dependent manner. SIRT1 antagonist or agonist and CGRP or antagonist treatment further confirmed the result. Conclusion. Our findings indicate PD1 has a potent analgesic effect, and can modulate neuro-inflammation by regulating SIRT1-mediated CGRP signaling in NCLDH.

Biological differences and molecular mechanism of different peripheral nerves after injury.

The aim of the study was to analyze the apoptosis of neurons and the differences in expression of Bcl-2 and Bax protein in the neurons in the corresponding spinal cord segment after the repair of the tibial nerve (TN) and common peroneal nerve (CPN) in rats. 126 healthy male Sprague-Dawley (SD) rats aged 7-8 weeks were randomly divided into group A (control group), group B (TN was cut and sutured), and group C (CPN was cut and sutured), with 42 rats in each group. The spinal cord tissues of rats in different groups were stained with hematoxylin-eosin (HE) on the 1st, 3rd, 7th, 14th, 21st, and 28th day after surgery; the number of neurons in anterior horn of spinal cord, axon density (AD), axon passage rate (APR), and recovery rate (RR) of muscle cell cross-sectional area (MCCA) were calculated; and differences in the expression of Bcl-2 and Bax proteins in the three groups of rats were analyzed by immunohistochemistry. The results showed that there was no statistically significant difference in the muscle wet weight (MWW) RR of the three groups of rats on the 14th day after the surgery (p>0.05), and the MWW RRs of rats in groups B and C were higher at the 28th day after surgery in contrast to group A (p<0.05). The number of motor neurons in the anterior horn of spinal cord in group B was higher than that in group C at the 3rd, 7th, 14th, and 21st day after surgery (p<0.05); the MWW RR, MCCA, and CSARR of rats in group B were lower than those in group C (p<0.05); the proximal AD, distal AD, and APR in group B were higher than those of group C on the 14th and 28th day after the surgery (p<0.05); and there were no positive staining results in the spinal cord tissue of rats in group A after staining. The expressions of Bcl-2 and Bax in group B were higher observably than the expressions in group C (p<0.05), which indicated that the recovery ability of TN was stronger than that of the CPN; the expression of Bcl-2 and Bax in TN was notably higher than that of the CPN. The expression of Bcl-2 and Bax was related to cell apoptosis and nerve regeneration after nerve injury. It provided a reference basis for clinical diagnosis and treatment of peripheral nerves.

Small G-Protein Rheb Gates Mammalian Target of Rapamycin Signaling to Regulate Morphine Tolerance in Mice.

Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on μ-opioid receptors and downstream of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. The hypothesis was that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance. Male and female wild-type C57BL/6J mice or transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or morphine twice daily at 12-h intervals for 5 consecutive days to establish a tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. After 5 days, the spine was harvested for Western blot or immunofluorescence analysis. Chronic morphine administration resulted in the upregulation of spinal Rheb by 4.27 ± 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb impaired morphine analgesia, resulting in a tail-flick latency of 4.65 ± 1.10 s (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice (10 ± 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 signaling by rapamycin potentiated morphine-induced tolerance (maximum possible effect, 52.60 ± 9.56% in the morphine + rapamycin group vs. 16.60 ± 8.54% in the morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 5'-monophosphate-activated protein kinase inhibited Rheb upregulation and retarded the development of morphine-dependent tolerance (maximum possible effect, 39.51 ± 7.40% in morphine + metformin group vs. 15.58 ± 5.79% in morphine group; P < 0.0001). This study suggests spinal Rheb as a key molecular factor for regulating mammalian target of rapamycin signaling.

Suppression of neuropathic pain in the circadian clock-deficient Per2m/m mice involves up-regulation of endocannabinoid system.

Neuropathic pain often results from injuries and diseases that affect the somatosensory system. Disruption of the circadian clock has been implicated in the exacerbation of the neuropathic pain state. However, in this study, we report that mice deficient in a core clock component Period2 (Per2m/m mice) fail to develop tactile pain hypersensitivity even following peripheral nerve injury. Similar to male wild-type mice, partial sciatic nerve ligation (PSL)-Per2m/m male mice showed activation of glial cells in the dorsal horn of the spinal cord and increased expression of pain-related genes. Interestingly, α1D-adrenergic receptor (α1D-AR) expression was up-regulated in the spinal cord of Per2m/m mice, leading to increased production of 2-arachidonoylglycerol (2-AG), an endocannabinoid receptor ligand. This increase in 2-AG suppressed the PSL-induced tactile pain hypersensitivity. Furthermore, intraspinal dorsal horn injection of adeno-associated viral vectors expressing α1D-AR also attenuated pain hypersensitivity in PSL-wild-type male mice by increasing 2-AG production. Our findings reveal an uncovered role of the circadian clock in neuropathic pain disorders and suggest a link between α1D-AR signaling and the endocannabinoid system.

The role of neuroinflammation in the transition of acute to chronic pain and the opioid-induced hyperalgesia and tolerance.

Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state. Neuroinflammation has been proven to be a fundamental mechanism in the genesis of acute pain and its transition to neuropathic and chronic pain. A noxious event that stimulates peripheral afferent nerve fibers may also activate pronociceptive receptors situated at the dorsal root ganglion and dorsal horn of the spinal cord, as well as peripheral glial cells, setting off the so-called peripheral sensitization and spreading neuroinflammation to the brain. Once activated, microglia produce cytokines, chemokines, and neuropeptides that can increase the sensitivity and firing properties of second-order neurons, upregulating the signaling of nociceptive information to the cerebral cortex. This process, known as central sensitization, is crucial for chronification of acute pain. Immune-neuronal interactions are also implicated in the lesser-known complex regulatory relationship between pain and opioids. Current evidence suggests that activated immune and glial cells can alter neuronal function, induce, and maintain pathological pain, and disrupt the analgesic effects of opioid drugs by contributing to the development of tolerance and dependence, even causing paradoxical hyperalgesia. Such alterations may occur when the neuronal environment is impacted by trauma, inflammation, and immune-derived molecules, or when opioids induce proinflammatory glial activation. Hence, understanding these intricate interactions may help in managing pain signaling and opioid efficacy beyond the classical pharmacological approach.

The mechanism of manual muscle testing as proposed by the ventral horn theory

It is hypothesized that the central integrative state (CIS) of the spinal cord’s ventral horn depends upon myriad inputs from primary afferentation secondary to gravitational perturbation of joint mechanoreceptors. Further, the current perspective of manual muscle testing (MMT) and diagnostic muscle testing (DMT) research—each being universially accepted by the medical community—tends to focus exclusively on the conditional state of the muscle and/or the α-motoneuron affecting that muscle. Diagnostic muscle testing, however, is mainly an assessment tool for functional disorders. Moreover, since the human brain is receptor dependent, the entirety of the human neurological environment extends from the primary peripheral receptor and its subsequent action potential to the dosral root ganglion, dorsal horn of the spinal cord, and rostral neuroaxial centers like the cerebellum, midbrain, thalamus, and cortex—and ultimately to the effector, including all components in between. The human nervous system concerns itself with whole body reactions, not individual muscles. The premise here is that the highest primary afferentation is secondary to mechanoreceptor deformation after gravitational perturbation. The goal of treatment is to facilitate the patient’s highest level of human performance by recognizing and treating discrete pathology while avoiding an iatrogenic effect. Merely focusing on the α-motoneuron and/or its influence on the effector generates a myopic understanding that loses appreciation of efferent autonomic drive and structural performance. An individual muscle focus does not recognize the complexity of homologous involvement.

Synaptic circuits involving gastrin-releasing peptide receptor-expressing neurons in the dorsal horn of the mouse spinal cord.

The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be "tertiary pruritoceptors," conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.

RABGGTB plays a critical role in ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unknown causes, which mainly affects motor neurons in the anterior horn of the spinal cord, brain stem, and cerebral cortex, also known as motor neuron disease. An important pathological feature of ALS is the formation of aggregates of mutant SOD1 protein, CTF25 of TDP-43, or other abnormal proteins in motor neurons, which require autophagy for degradation. Protein prenylation is known to participate in membrane association and proper localization of proteins. RABGGTB is the β subunit of GGTase II (one of the prenyltransferases) that can regulate autophagy via Rab7 geranylgeranylation. In this study, we overexpressed RABGGTB via lentiviral transfection in NSC34-hSOD1G93A and TDP-43 cells. Overexpression of RABGGTB improved ALS cell proliferation by facilitating autophagosome–lysosome fusion. Furthermore, the abnormal aggregation of SOD1 protein was reduced. This indicates that protein prenylation is important for the proliferation and autophagy of cells autophagy. Enhanced autophagy has been observed in two of the most widely used ALS cell models. These findings indicate the widespread applicability of prenylation in ALS. In summary, overexpression of RABGGTB improved the geranylgeranylation of the Rab7 protein and had a positive effect on cells. These findings provide insights into the development of a novel therapeutic strategy for ALS.

Neurotropin Alleviates Bortezomib-Induced Neurotoxicity Via Microglial Neuroinflammation

Objective: To investigate the effect of neurotropin (NTP) on the prevention and amelioration of neurotoxicity induced by bortezomib (BTZ)-based chemotherapy regimens and the possible mechanism of action, and to provide new ideas for the prevention mechanism and treatment of bortezomib-induced peripheral neuropathy (BIPN). Methods: The BIPN model was constructed by injecting bortezomib （ BTZ group ）or bortezomib+saline ( BTZ+NS group)into the tail vein of C57BL/6 mice. After successful modeling, NTP was added to take intraperitoneal injections for 4 weeks, which were defined to be NTP group. In order to assess the severity of BIPN, systemic toxicity, pain behavioral and sensorimotor kinetic changes in mice of different group were observed while transmission electron microscopy examination was used to observe the damage of peripheral nerve ultrastructure and myelin thickness. Immunofluorescence staining method was used to detected the activation of spinal cord microglial and their expression level of inflammatory factors such as IL-1β, IL-6 and TNF-α. ELISA was used to detected the expression of IL-1β, IL-6 and TNF-α in the dorsal horn homogenate of the spinal cord; Western blot to detect the protein expression of pathway-associated proteins JAK/STAT. Results: The Compared with the Control group, the BTZ and BTZ+NS groups showed significant decreases in mechanical, thermal pain thresholds and motor coordination compared with the Control group (P&amp;lt;0.05), and ultrastructural damage to the peripheral nerves, with demyelinating lesions and a significant reduction in the overall thickness of myelin sheaths in myelinated fibers (0.62±0.08 Vs 0.56±0.12, P＜0.01). NTP administration significantly improved pain behavioral changes, reduced ultrastructural damage, reversed demyelinating lesions and significantly increased myelin thickness (0.56±0.06 Vs 0.62±0.08, P＜0.01) in model mice compared with BTZ group. Immunofluorescence staining suggested that microglia in the dorsal horn of the spinal cord of mice in the BTZ group and the BTZ+NS group were significantly activated, which were shown the fluorescence ratio of IBA-1 + was significantly increased (2.55±0.61 Vs 0.55±0.04，2.42±0.89 Vs 0.55±0.04，P＜0.0001), while NTP significantly improved the activation of microglia in the model mice (0.71±0.13 Vs 2.55±0.61, 0.71±0.13 Vs 2.42±0.89, P&amp;lt;0.0001). The co-staining results suggest that the increase in inflammatory factors may originate from microglia. ELISA results that the expression level of IL-6 and TNF-α in NTP administration group significantly decreased compared with the group of BTZ group (IL-6: 37.87±23.2 Vs 111.8±6.0, P＜0.05; TNF-α: 547.9±17.11 Vs 998.8±333.4, P＜0.05) and the BTZ+NS group (IL-6: 37.87±23.2 Vs 88.3±15.58, P&amp;lt;0.05; TNF-α: 547.9±17.11 Vs 768.3±37.45, P&amp;lt;0.05) in the dorsal horn homogenate of the spinal cord. The results of spinal cord proteomics showed that neurotropin could induce the changes of differential proteins, such as PI3K-AKT, MAPK, JAK/STAT, which were related to inflammation. Moreover, these differential proteins can be significantly enriched in the JAK/STAT KEGG Pathway. The KEGG pathway of differential protein enrichment in the spinal cord of differential BIPN mice was detected by proteomics chip after NTP treatment, and the JAK/STAT pathway was significantly down-regulated after NTP treatment. Western blot showed that the protein expression of JAK1/STAT3 decreased after NTP administration. Conclusion: Neurotropin alleviates bortezomib induced neurotoxicity through microglial neuroinflammation, and may reduce the release of glial inflammation by regulating JAK1/STAT3 signaling pathway, thus playing a therapeutic role in BIPN. Repeated experiments are needed for further research. Keywords: Neurotropin, Bortezomib, Peripheral neuropathy, Neuroinflammation

GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain

BackgroundCancer pain has a significant impact on patient’s quality of life. Astrocytes play an important role in cancer pain signaling. The direct targeting of astrocytes can effectively suppress cancer pain,...

Microglial Refinement of A-Fiber Projections in the Postnatal Spinal Cord Dorsal Horn Is Required for Normal Maturation of Dynamic Touch.

Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganization, including the refinement of primary afferent A-fiber terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here, we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fiber terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fiber refinement and elimination, resulting in an altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioral hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fiber projections remain in the dorsal horn, and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch.

Phenocopy of Amyotrophic Lateral Sclerosis in Patients with Chiari 1 Malformation Associated Syringomyelia: Brief Literature Review

Arnold-Chiari malformation or Chiari malformation (CM1) is the name of a group of deformities of the posterior fossa and hindbrain (cerebellum, pons and medulla oblongata). The pathogenetic basis of this disease is associated with herniation of the cerebellar tonsils through the foramen magnum. CM1 is classified as a rare disease. CM1 can present with a wide variety of symptoms, also non-specific, with consequent controversies on diagnosis and surgical decision-making, particularly in asymptomatic or minimally symptomatic. Syringomyelia (Syr), hydrocephalus, craniocervical instability, encephalocele, scoliosis, spina bifida and spinal dysraphism are the most common comorbidities that may present at the time of diagnosis or develop secondarily. Most attention has been paid to syringomyelia complicated by CM1 (CM1-related Syr). Formation of single or multiple fluid-filled cavities in the spinal cord and/or bulb as a result of pulse changes in intracranial pressure associated with disruption of normal cerebrospinal fluid circulation due to morphological abnormalities of the brain at the magnum level. This condition can be complicated by a rarer disease caused by the development of damage to the anterior horns of the spinal cord - amyotrophic sclerosis (ALS syndrome). In this brief literature review we are trying to demonstrate the mean pathogenic basis of amyotrophic lateral sclerosis in patients with chiari 1 malformation associated syringomyelia.

Conventional Remedy to Lou Gehrig’s Disease - Amyotrophic Lateral Sclerosis (ALS): A Rare Clinical Entity

Lou Gehrig’s disease, commonly known as amyotrophic lateral sclerosis, is an incredibly rare clinical condition that affects about 5 in 100,000 people annually in India, making it one of the rarest diseases in the entire world. With an average age of 55, this disease typically impacts people between the ages of 40 and 70. Males are more prone to develop the condition. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extramotor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. Typically, patients report difficulties swallowing or a shift in voice pitch while speaking due to tongue involvement. Initial ALS symptoms can resemble those of other neuromuscular illnesses and are completely non-specific. In this case report, we described a 44-year-old gentleman who has been diagnosed with Amyotrophic Lateral Sclerosis in accordance to an MRI scan describing symptoms like unable to speak, reduced tongue movements, trouble swallowing, excessive salivation, swelling over the tongue and loss of tongue tone for the past three to four months. The present study discusses the clinical presentation, diagnosis, therapeutic regimen and prognosis. Both allopathic and ayurvedic oral medications with local therapeutic regimens like Jivha Pratisarana (Rubbing of dry powder on tongue) and Nasya (nasal drops of medicated oil) were employed in the patient which have satisfactory results enhancing for betterment of lifestyle.

Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis.

Neuroinflammation, and specifically microglia, plays an important but not-yet well-understood role in the pathophysiology of amyotrophic lateral sclerosis (ALS), constituting a potential therapeutic target for the disease. Recent studies have described the involvement of different microglial transcriptional patterns throughout neurodegenerative processes, identifying a new state of microglia: disease-associated microglia (DAM). The aim of this study is to investigate expression patterns of microglial-related genes in ALS spinal cord. We analyzed mRNA expression levels via RT-qPCR of several microglia-related genes in their homeostatic and DAM state in postmortem tissue (anterior horn of the spinal cord) from 20 subjects with ALS-TDP43 and 19 controls donors from the Navarrabiomed Biobank. The expression levels of TREM2, MS4A, CD33, APOE and TYROBP were found to be elevated in the spinal cord from ALS subjects versus controls (p-value < 0.05). However, no statistically significant gene expression differences were observed for TMEM119, SPP1 and LPL. This study suggests that a DAM-mediated inflammatory response is present in ALS, and TREM2 plays a significant role in immune function of microglia. It also supports the role of C33 and MS4A in the physiopathology of ALS.

Clinical and epidemiological characteristics of acute flaccid myelitis cases in children registered in the Russian Federation in 2015–2019

Acute flaccid myelitis is a syndrome characterized as the development of acute flaccid paralysis of one or more limbs due to lesions of the anterior horns of the spinal cord, which occurs against the background of a viral infection. More than 300 acute flaccid paralysis cases are registered in the Russian Federation annually, most of them are of a non-infectious etiology. In some cases, patients develop a complex of symptoms similar to poliomyelitis, but without isolation of polioviruses from stool samples. Clinical characteristics of such cases include acute onset, fever, persistent peripheral asymmetric paresis/paralysis of predominantly proximal parts of the limbs, and absence of pathological reflexes, pelvic disturbances, or pyramidal symptoms. In literature, such complex of symptoms is referred as acute flaccid myelitis. We provide an analysis of 18 cases of acute flaccid myelitis detected in the Russian Federation in the period from 2015 to 2019. A clear seasonality of the disease from July to November was noted. Studies of faecal samples, cerebrospinal fluid and blood samples did not reveal the pathogen. In all patients, regardless of therapy, there was a positive trend, but complete recovery was not achieved: paresis of varying severity persisted, mainly in the proximal extremities Therefore, acute flaccid myelitis cases as acute flaccid paralysis cases of unknown etiology require an additional observation and an expanded algorithm of laboratory investigation aimed to finding a possible pathogen.

Effect of electroacupuncture intervention on the spinal cord PPIA/NF-κB signaling pathway in mice with amyotrophic lateral sclerosis.

To observe the effects of electroacupuncture (EA) on motor function, expression of extracellular cyclophile A(PPIA) and PPIA/nuclear factor-κB (NF-κB) signaling pathway in spinal cord of amyotrophic la-teral sclerosis (ALS) mice, so as to explore the mechanism of EA intervention in regulating extracellular PPIA on neuroinflammation in ALS mice. Thirty ALS-SOD1G93A mice with hSOD1-G93A gene were randomly divided into model, EA and Riluzole groups , with 10 mice in each group, and other 10 ALS-SOD1G93A negative mice were used as the blank group. EA was applied to bilateral "Yanglingquan"(GB34) and "Zusanli"(ST36) for 20 min once daily, 5 days a week for 2 weeks. In the Riluzole group, riluzole solution (30 mg·kg-1·d-1) was administrated intragastrically, and the treatment time was the same as that in the EA group.Rotating rod experiment and open field experiment were used to evaluate the changes in motor function of mice .The morphology of motor neurons in the anterior horn of spinal cord was observed by HE staining.The relative protein expression levels of PPIA, TDP-43 and NF-κB in the spinal cord were detected by Western blot.The positive expression level of TDP-43 in the spinal cord was detected by immunohistochemistry. The positive expression level of PPIA in spinal cord was marked by immunofluorescence. Serum PPIA content was determined by ELISA. Compared with the blank group, the time of rod dropping and the total distance of open field movement in the model group were shortened (P<0.01), the number of motor neurons in the anterior horn of the spinal cord was reduced, the cell morphology was incomplete, the cell body was atrophied, the protein expression and positive expression of TDP-43 were increased (P<0.01), the protein expressions of PPIA and NF-κB in the spinal cord were increased(P<0.01), the serum content of PPIA and immunofluorescence expression of PPIA in spinal cord were increased (P<0.01). Compared with the model group, the time of rod dropping and the total distance of open field movement of mice in the EA group and the Riluzole group were prolonged (P<0.05, P<0.01), and the injury of motor neuron in the anterior horn of the spinal cord was decreased, the protein expression and positive expression of TDP-43 in the spinal cord were decreased (P<0.05, P<0.01)；the relative expression levels of PPIA and NF-κB proteins were decreased (P<0.05, P<0.01), and the content of PPIA in serum and the immunofluorescence expression of PPIA in the spinal cord were decreased (P<0.05, P<0.01) in the EA group；the relative protein expression of NF-κB and fluorescence expression of PPIA in spinal cord of mice in the Riluzole group were decreased (P<0.05). EA intervention can improve motor function in ALS mice, and its mechanism may be related to the inhibition of PPIA/NF-κB signaling pathway by EA to alleviating neuroinflammatory response.

Enhancing fentanyl antinociception and preventing tolerance with α-2 adrenoceptor agonists in rats

Fentanyl (FEN) is a potent opioid analgesic used for pain management. Opioid analgesic tolerance poses a significant challenge to the clinical utility of opioid agonists. Preventing the development of tolerance to opioid analgesia is crucial for improving its efficacy and safety. The noradrenergic system is involved in pain regulation. This study examined the effects of α-2 adrenoceptor (AR) agonists, dexmedetomidine (DEX), and xylazine (XYL) on FEN tolerance and antinociception, and their impact on μ-opioid receptor (MOR) expression in the posterior horn of the spinal cord (SC). Male rats were divided into six groups and treated with different drug combinations for three consecutive days. Analgesia tests and motor performance assessments were conducted, followed by SC analysis using immunohistochemistry (IHC). Analgesia tests revealed the development of FEN tolerance on the second day, but the groups receiving combined drugs did not develop tolerance. Instead, FEN antinociception was enhanced, with a prolonged duration of its effects. None of the drugs caused sedation or motor impairment, and SC morphology appeared normal. MOR expression levels did not differ significantly between the groups based on IHC analysis. These findings suggest that changes in the secondary messenger system may play a role in the early development of FEN tolerance. Combining drugs can prevent tolerance, while enhancing FEN's antinociceptive effects. These results have promising implications for chronic pain management; however, further research is needed to explore the molecular effects of α-2 AR agonists on FEN tolerance. Overall, this study sheds light on the mechanism of FEN tolerance and identifies potential avenues for future research.