Peripheral Nerve Disease Research Articles

Infantile Krabbe disease (0-12 months), progression, and recommended endpoints for clinical trials.

Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile-onset (0-12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints. Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan-Meier survival curves were used for analysis. One hundred and thirty-seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty-three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years. Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies.

Peripheral Neuropathic Pain.

This article synthesizes current knowledge on neuropathic pain, with a brief review of mechanisms, diagnostic approaches, and treatment strategies to help neurologists provide effective and individualized care for patients with this complex condition. The most promising developments in peripheral neuropathic pain are related to the molecular biology of the peripheral nervous system. Systematic molecular and genetic analyses of peripheral nerve terminals and dorsal root ganglia have advanced our understanding of the genetics of function and disease of peripheral nerves, as well as their physiology and clinical manifestations. Peripheral neuropathic pain, similar to central neuropathic pain, is primarily influenced by the biology and pathophysiology of the underlying structures, peripheral sensory nerves, and their central pathways. The clinical course is widely variable in sensory symptoms and intensities, natural history, and response to treatments.

THE UTILITY OF THE NORMAL THIN SECTION SKIN BIOPSY IN THE ASSESSMENT OF SYSTEMIC/EXTRACUTANEOUS DISEASE

Diseases reflective of multiorgan vascular injury of diverse etiology, peripheral nerve disease, dysautonomia syndromes and intravascular lymphoma malignancies may potentially exhibit abnormalities on a normal skin biopsy that may be instrumental in establishing a diagnosis. A retrospective review of our data base was conducted to uncover cases where a normal skin biopsy was performed to rule in or out certain systemic diseases such as complement driven thrombotic microvascular disease including atypical hemolytic uremic syndrome, post transplant thrombotic microangiopathy, and severe/critical COVID-19, systemic capillary leak syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) intravascular B cell lymphoma, dysautonomia syndromes and mast cell activation syndrome. Immunohistochemical stains were conducted inclu C5b-9, CD56, MXA, B and T cell markers. There were expected patterns critical in establishing diagnosis based on evaluating certain parameters including assessing for increased C5b-9 microvascular deposition from the deltoid area(atypical hemolytic uremic syndrome, post-transplant thrombotic microangiopathy, catastrophic antiphospholipid antibody syndrome and severe/critical COVID-19), enhanced type I interferon signaling (systemic capillary leak syndrome), ultrastructural arteriopathic changes (CADASIL),lower extremity reduced cutaneous autonomic innervation (small fiber neuropathy and POTS), abdominal, thigh and buttock skin for the presence of intravascular lymphocytes on biopsy(intravascular B cell lymphoma), distinct structural changes in elastic fibers supportive of pseudoxanthoma elasticum and a higher than normal density of mast cells in the absence of other inflammatory cell types (mast cell activation syndrome). The skin is a critical window for understanding disease, a concept well exemplified by the myriad of diseases that can be suggested by the microscopic and or ultrastructural examination of clinically normal skin, hence establishing the normal skin biopsy as an important tool for understanding extracutaneous disease.

Automated peripheral nerve segmentation for MR-neurography

BackgroundMagnetic resonance neurography (MRN) is increasingly used as a diagnostic tool for peripheral neuropathies. Quantitative measures enhance MRN interpretation but require nerve segmentation which is time-consuming and error-prone and has not become clinical routine. In this study, we applied neural networks for the automated segmentation of peripheral nerves.MethodsA neural segmentation network was trained to segment the sciatic nerve and its proximal branches on the MRN scans of the right and left upper leg of 35 healthy individuals, resulting in 70 training examples, via 5-fold cross-validation (CV). The model performance was evaluated on an independent test set of one-sided MRN scans of 60 healthy individuals.ResultsMean Dice similarity coefficient (DSC) in CV was 0.892 (95% confidence interval [CI]: 0.888–0.897) with a mean Jaccard index (JI) of 0.806 (95% CI: 0.799–0.814) and mean Hausdorff distance (HD) of 2.146 (95% CI: 2.184–2.208). For the independent test set, DSC and JI were lower while HD was higher, with a mean DSC of 0.789 (95% CI: 0.760–0.815), mean JI of 0.672 (95% CI: 0.642–0.699), and mean HD of 2.118 (95% CI: 2.047–2.190).ConclusionThe deep learning-based segmentation model showed a good performance for the task of nerve segmentation. Future work will focus on extending training data and including individuals with peripheral neuropathies in training to enable advanced peripheral nerve disease characterization.Relevance statementThe results will serve as a baseline to build upon while developing an automated quantitative MRN feature analysis framework for application in routine reading of MRN examinations.Key PointsQuantitative measures enhance MRN interpretation, requiring complex and challenging nerve segmentation.We present a deep learning-based segmentation model with good performance.Our results may serve as a baseline for clinical automated quantitative MRN segmentation.Graphical

InspireGBs - Inspiratory muscle training in people with Guillain-Barré syndrome: A feasibility study.

Guillain-Barré syndrome (GBS) is a rare immune-mediated peripheral nerve disease often preceded by infections. Respiratory muscle weakness is a common complication in this population, leading to decreased vital capacity, weakened coughing ability, atelectasis, and pulmonary infections. Inspiratory muscle training (IMT) has been widely used to enhance inspiratory muscle strength and pulmonary function in various diseases; however, its application in GBS is unknown. To assess the safety, feasibility, and preliminary effectiveness of an IMT protocol-InspireGBs-in people with GBS. A pre/post feasibility study was conducted. Feasibility was determined by participant recruitment/retention, adherence, time spent in each session, and adverse events. Secondary outcome was inspiratory muscle strength. InspireGBs consisted of twice daily sessions 5 times/week, three sets of 10 breaths in each session, for 6 weeks. Initial resistance was set at 50% of participant's baseline maximal inspiratory pressure (MIP) and with a weekly increase of 10% calculated from the previous week's training intensity, if tolerated, otherwise the increase was 5%. Eleven patients (63% male; 63 ± 9 years) were recruited from inpatient rehabilitation and 10 completed the study. Recruitment and retention rates were high (79% and 91%, respectively). Excellent adherence rate (96%) was obtained with no reported adverse effects or safety issues. Sessions lasted from 4 to 6 minutes. The MIP improved (pretraining: 39 [26.5-50] cm H2O vs. posttraining: 61 [56.3-64.5] cm H2O, p = .005 and pretraining: 38 [30.5-53.8] % of predicted vs. posttraining: 60 [54.28-71.58] % of predicted, p = .009) with the InspireGBs. InspireGBs is safe, feasible, and may be effective in improving inspiratory muscle strength in individuals with GBS. A randomized controlled trial is now needed to strengthen these findings.

Initial findings using high-resolution magnetic resonance imaging for visualisation of the sural nerve and surrounding anatomy in healthy volunteers at 7 Tesla.

Histopathological diagnosis is the gold standard in many acquired inflammatory, infiltrative and amyloid based peripheral nerve diseases and a sensory nerve biopsy of sural or superficial peroneal nerve is favoured where a biopsy is deemed necessary. The ability to determine nerve pathology by high-resolution imaging techniques resolving anatomy and imaging characteristics might improve diagnosis and obviate the need for biopsy in some. The sural nerve is anatomically variable and occasionally adjacent vessels can be sent for analysis in error. Knowing the exact position and relationships of the nerve prior to surgery could be clinically useful and thus reliably resolving nerve position has some utility. 7T images of eight healthy volunteers' (HV) right ankle were acquired in a pilot study using a double-echo in steady-state sequence for high-resolution anatomy images. Magnetic Transfer Ratio images were acquired of the same area. Systematic scoring of the sural, tibial and deep peroneal nerve around the surgical landmark 7 cm from the lateral malleolus was performed (number of fascicles, area in voxels and mm2, diameter and location relative to nearby vessels and muscles). The sural and tibial nerves were visualised in the high-resolution double-echo in steady-state (DESS) image in all HV. The deep peroneal nerve was not always visualised at level of interest. The MTR values were tightly grouped except in the sural nerve where the nerve was not visualised in two HV. The sural nerve location was found to be variable (e.g., lateral or medial to, or crossing behind, or found positioned directly posterior to the saphenous vein). High-resolution high-field images have excellent visualisation of the sural nerve and would give surgeons prior knowledge of the position before surgery. Basic imaging characteristics of the sural nerve can be acquired, but more detailed imaging characteristics are not easily evaluable in the very small sural and further developments and specific studies are required for any diagnostic utility at 7T.

Clinical and Electrophysiologic Findings of Fatigue in Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Narrative Review

ABSTRACT Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disease with progressive or recurrent motor and sensory symptoms lasting over 2 months. The condition is autoimmune and is diagnosed through clinical, electrodiagnostic, and laboratory features. This narrative review aims to summarize the latest findings on fatigue in CIDP, including its prevalence, factors that influence its severity, origin, and management strategies. Until May 20th, 2023, the English medical literature was searched with the keywords: “CIDP,” and “fatigue.” Study design, patient group, clinical findings related to CIDP and fatigue, treatment, and current status information were extracted from each study. One reviewer conducted research and screening, and another conducted the review process. Studies in English, including original studies and case series involving a minimum of five patients, were included until May 20th, 2023. Fatigue is a common symptom in CIDP, although not specific to the disease, and profoundly impacts the patient’s quality of life. The mechanisms specific to fatigue in CIDP are still unknown. However, we suggest that fatigue is not solely a residual symptom and may be related to inflammatory conditions. Further research is needed, specifically on the central origin of fatigue. It is essential to analyze the novel treatment options for fatigue in CIDP because it is a significant contributing factor to morbidity.

Recent insights into haematology and peripheral nerve disease.

The association between clonal haematological disorders and peripheral nerve disease is recognized. Paraproteinaemic phenomena are the most common mechanism, but direct neural lymphomatous infiltration is seen and can be challenging to diagnose. Traditional and novel anticancer therapies have neuropathic side effects. Novel studies using sensitive techniques are refining the incidence of peripheral neuropathy in patients with a monoclonal gammopathy, and the pathogenesis of IgM Peripheral neuropathy (PN) and POEMS syndrome. Recent series give insight into the characteristics and diagnostic challenges of patients with neurolymphomatosis and amyloid light chain amyloidosis. There is an increasing repertoire of effective anticancer drugs in haematological oncology, but chemotherapy-related neuropathy remains a common side effect. This review of the current literature focuses on recent updates and developments for the paraproteinaemic neuropathies, and the evaluation, diagnosis and treatment of peripheral nerve disease due to high-grade and low-grade lymphomas and lymphoproliferative disorders.

How to Perform Autoantibody Testing for Autoimmune and Inflammatory Diseases of Peripheral Nerves and Muscles

Measurement of autoantibodies is essential for the management of several peripheral nerve and muscle diseases. The clinical significance of autoantibody testing differs for each antibody. In addition, clinicians must understand several issues including the accuracy of the test, isotype and subclass distribution, and its relationship to disease activity. Moreover, many autoantibody tests are not covered by health insurance. With limited medical resources, clinicians are required to be up-to-date with the latest information to utilize test results in daily practice without misunderstanding.

Enhancing Neuromuscular Disease Diagnosis through Electrophysiology

Electrophysiologic testing plays an important role in evaluating peripheral nerve, muscle, and neuromuscular junction diseases, aiding in diagnosis and treatment strategies by offering real-time assessment. Demyelination of peripheral nerves results in increased conduction delay, temporal dispersion, conduction block, and stimulation threshold. The localization or diffusion of these changes is crucial in understanding disease pathogenesis, necessitating stimulation at multiple points along nerve pathways. When axonal degeneration occurs, the amplitude is reduced, with mild conduction delay. Acute axonal degeneration may require 1 week to develop into Wallerian degeneration. During this time, conductivity was preserved in the nerve peripheral to the lesion. When MG or LEMS is suspected, repetitive nerve stimulation tests and single-fiber EMG are valuable for the diagnosis and pathophysiological evaluation. Notably, the latter is highly sensitive but not specific. Needle electromyography (EMG) assists in differentiating between myopathies and neurogenic diseases, and in determining whether the patient is in an acute or chronic stage. Integration of these tests contribute to an accurate diagnosis when considering the presenting symptoms.

Utilization of Peripheral Neuropathology Tests

Neuropathological findings rarely lead to a definitive diagnosis of autoimmune and inflammatory peripheral nerve diseases, and indications for invasive nerve biopsy with subsequent disability should be carefully determined. In addition to disease-specific pathological findings, identifying findings that facilitate differential diagnosis in clinical practice is necessary. This article reviews the neuropathological findings that are valuable in the differential diagnosis of autoimmune and inflammatory peripheral nerve diseases.

Electrophysiological studies versus high-resolution nerve ultrasound in diagnosis of Guillain–Barré syndrome

Abstract Background Guillain–Barré syndrome (GBS) is polyneuropathy characterized by inflammation and immune-mediated processes that is classified into many subtypes based on electrophysiological and pathological criteria. The diagnosis of GBS can be confirmed using electrophysiological studies. However, electrophysiological studies may be normal when carried out early within 1 week in the course of the disease (Berciano et al. in J Neurol 264:221–236, 2017). One of the most useful imaging modalities for peripheral nerve diseases is ultrasonography (US). Nerve US in combination with electrophysiological studies provides an appropriate method in evaluating diseased peripheral nerves. This study aimed to enhance the reliability of early GBS diagnosis by correlating the findings of electrophysiological studies and nerve ultrasound. The nerve conduction studies (NCSs) in 37 GBS patients and 37 controls combined with cross-sectional area (CSA) assessment with US within the first 3 days of onset of symptoms and on day 14 after disease onset were evaluated. Results At presentation, patients and controls did not differ significantly in NCS parameters (p ≥ 0.05) except for a significantly longer F-wave minimum latency in the median, ulnar, and tibial nerves in patients (p < 0.001). While on day 14 all NCS parameters differed significantly in patients in comparison to controls (p < 0.001) with exception of the sural nerve parameters (p ≥ 0.05). Except for the sural nerve (p ≥ 0.05), all the examined nerves' CSAs were considerably higher in patients at presentation and on day 14 in comparison to the controls (p < 0.001). The subtypes of Guillain–Barré syndrome either demyelinating, axonal or mixed axonal and demyelinating did not significantly differ regarding the CSAs of all the examined nerves either at presentation or on day 14 (p > 0.05). Conclusion Electrophysiological results in GBS are crucial in diagnosing the disease and understanding its pathophysiology, but serial NCSs are required. Ultrasound shows structural aspects of the nerve, so ultrasonography is a reliable tool which can be used in diagnosis and follow-up of early GBS. As a result, combining the two investigations has a complementary effect in the diagnosis and prognosis of GBS.

Corneal Neuropathic Pain: A Patient and Physician Perspective.

Corneal neuropathic pain (CNP) is a debilitating condition characterized by pain in the absence of a noxious stimulus. Symptoms such as ocular stinging, burning, photophobia, irritation, and a deep aching pain can be severe despite a seemingly normal ocular surface on examination. CNP may develop due to either peripheral or central sensitization. Peripheral sensitization develops due to aberrant regeneration of corneal nociceptors and nerve fibers as a result of corneal injury or disease of peripheral corneal nerves. Whereas, central sensitization develops due to upregulation of excitatory neurotransmitters as a result of chronic inflammation, which leads to amplification of neuronal response to stimuli. Unfortunately, due to the disparity in severity of symptomology and the observable signs on examination, patients' symptoms are commonly thought to be "psychological" or "functional", and patients report feeling ignored and neglected. Additionally, diagnosis is often delayed which adversely affects patient outcomes. Research to date has focused on the scientific aspects of corneal neuropathic pain: its pathophysiology, epidemiology, investigations, and management. Research into the patient personal experience and the challenges faced by individual patients and their clinicians is lacking. We present the patient and physician perspective on the journey of both patients in order to provide insights into the challenges faced by patients and physicians in the diagnosis, assessment, and management of corneal neuropathic pain.

Combining PLGA microspheres loaded with Liver X receptor agonist GW3965 with a chitosan nerve conduit can promote the healing and regeneration of the wounded sciatic nerve.

Globally, peripheral nerve injury (PNI) is a common clinical issue. Successfully repairing severe PNIs has posed a major challenge for clinicians. GW3965 is a highly selective LXR agonist, and previous studies have demonstrated its positive protective effects in both central and peripheral nerve diseases. In this work, we examined the potential reparative effects of GW3965-loaded polylactic acid co-glycolic acid microspheres in conjunction with a chitosan nerve conduit for peripheral nerve damage. The experiment revealed that GW3965 promoted Schwann cell proliferation and neurotrophic factor release in vitro. In vivo experiments conducted on rats showed that GW3965 facilitated the restoration of motor function, promoted axon and myelin regeneration in the sciatic nerve, and enhanced the microenvironment of nerve regeneration. These results offer a novel therapeutic approach for the healing of nerve damage. Overall, this work provides valuable insights and presents a promising therapeutic strategy for addressing PNI.

A case report of peroneal muscle atrophy type 2A2 with central nervous system involvement as initial presentation

BackgroundCharcot-Marie-Tooth disease (CMT) is a group of single-gene hereditary diseases of peripheral nerve with high clinical variability and genetic heterogeneity. The typical clinical manifestations include progressive muscle weakness and muscle atrophy in the distal extremities, accompanied by disappearance of tendon reflexes and distal sensory disturbances. CMT2A2 (OMIM: 609260) is caused by the mutation of MFN2 (OMIM: 608507), is the most common type of axonal pattern. Although a small number of patients with X-linked CMT1 (CMT1X) present with central nervous system involvement, including reversible white matter lesions, it is rarely in CMT2A2.Case presentationA 3-year and 5-month-old girl had experienced motor lag, muscle tension, and abnormal gait for over a year. A reexamination of cranial MRI revealed an anterior enlargement of the abnormal signal range in the lateral ventricles and bilateral frontal lobes. And the whole exon sequencing showed that this girl carried a heterozygous missense mutation c.314C > T of MNF2 gene, inherited from her mother.ConclusionsIn this study, we retrospectively analyzed the clinical and molecular genetic findings of a child with Charcot-Marie-Tooth disease A2 with central nervous system involvement as the initial presentation, and explored its pathogenic mechanism.

Chapter 2 - The role of imaging in focal neuropathies

Electrodiagnostic testing (EDX) has been the diagnostic tool of choice in peripheral nerve disease for many years, but in recent years, peripheral nerve imaging has been used ever more frequently in daily clinical practice. Nerve ultrasound and magnetic resonance (MR) neurography are able to visualize nerve structures reliably. These techniques can aid in localizing nerve pathology and can reveal significant anatomical abnormalities underlying nerve pathology that may have been otherwise undetected by EDX. As such, nerve ultrasound and MR neurography can significantly improve diagnostic accuracy and can have a significant effect on treatment strategy. In this chapter, the basic principles and recent developments of these techniques will be discussed, as well as their potential application in several types of peripheral nerve disease, such as carpal tunnel syndrome (CTS), ulnar neuropathy at the elbow (UNE), radial neuropathy, brachial and lumbosacral plexopathy, neuralgic amyotrophy (NA), fibular, tibial, sciatic, femoral neuropathy, meralgia paresthetica, peripheral nerve trauma, tumors, and inflammatory neuropathies.

Steroid-responsive Multifocal Motor Neuropathy with Cranial Manifestations

The typical presentation of multifocal motor neuropathy (MMN) is progressive asymmetric limb weakness. Cranial neuropathy is rare. We report a 28-year-old woman with cranial and bulbar palsies but with typical electrophysiological features of MMN by multifocal motor conduction blocks and serological markers of anti-ganglioside GM1 antibodies. The previous consensus on the treatment of MMN is intravenous immunoglobulins, but our patient responded to oral steroids and had clinical and electrophysiological improvement under continuous low-dose prednisolone treatment. In summary, MMN is a treatable chronic inflammatory disease of peripheral nerves. Cranial neuropathies can be its initial presentation. Electromyography studies are crucial for MMN diagnosis and helpful in monitoring disease activity and treatment responses. Although the previous guideline did not suggest using steroids for MMN, with careful patient selection, low-dose oral steroids can be an effective treatment in patients with relatively minor symptoms.

Preclinical Efficacy of Peripheral Nerve Regeneration by Schwann Cell-like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells in C22 Mice.

Charcot-Marie-Tooth disease (CMT) is a hereditary disease with heterogeneous phenotypes and genetic causes. CMT type 1A (CMT1A) is a type of disease affecting the peripheral nerves and is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene. Human tonsil-derived mesenchymal stem cells (TMSCs) are useful for stem cell therapy in various diseases and can be differentiated into Schwann cell-like cells (TMSC-SCs). We investigated the potential of TMSC-SCs called neuronal regeneration-promoting cells (NRPCs) for peripheral nerve and muscle regeneration in C22 mice, a model for CMT1A. We transplanted NRPCs manufactured in a good manufacturing practice facility into the bilateral thigh muscles of C22 mice and performed behavior and nerve conduction tests and histological and ultrastructural analyses. Significantly, the motor function was much improved, the ratio of myelinated axons was increased, and the G-ratio was reduced by the transplantation of NRPCs. The sciatic nerve and gastrocnemius muscle regeneration of C22 mice following the transplantation of NRPCs downregulated PMP22 overexpression, which was observed in a dose-dependent manner. These results suggest that NRPCs are feasible for clinical research for the treatment of CMT1A patients. Research applying NRPCs to other peripheral nerve diseases is also needed.

Approach to non-compressive myeloneuropathy through a rendezvous of 11 cases from an Indian backdrop

IntroductionMyeloneuropathy is a diagnosis ascribed to disorders that concomitantly affect the spinal cord and peripheral nerves. Recognizing this syndrome may sometimes be arduous, even for the most consummate clinicians, because symptomatology can mimic either spinal cord or peripheral nerve disease. Besides, examination findings suggest a predominantly myelopathic or neuropathic picture. This article reports a rendezvous of rare cases of clinically diagnosed myeloneuropathy with different etiological backgrounds and therapeutic responses. MethodsEleven cases of non-compressive myeloneuropathy were admitted to the Department of General Medicine of Burdwan Medical College and Hospital, Burdwan, West Bengal, India, between May 2018 and May 2022. ResultsWe report the cases of 11 patients (6 men and 5 women) who presented with myeloneuropathy of different etiologies (vitamin B12, copper, and vitamin E deficiencies, organophosphate poisoning, chronic alcohol abuse, illicit substances abuse, anti-thyroid peroxidase/anti-thyroglobulin antibody-related neurologic disorder responsive to steroids, Sjögren syndrome, chikungunya infection, paraneoplastic, and hereditary). ConclusionMeticulous historical analysis, careful clinical examination, and apposite utilization and interpretation of biochemical, electrophysiological, and neuroimaging findings are sine-qua-non for an accurate and consistent approach to evaluating a suspected case of myeloneuropathy, facilitating early treatment and recovery. Differential identification of these disorders needs an in-depth perception of the mode of onset of symptoms, the course of progression of the disease, the pattern of myelopathic/neuropathic findings, and recognition of other neurological or systemic manifestations. For untroubled understanding, etiologies of myeloneuropathies should be subdivided into a few broad categories, e.g., metabolic (nutritional), toxic (toxin-induced), infectious, inflammatory (immune-mediated), paraneoplastic, and hereditary disorders.

Plasma metabonomic study on the effect of Para‑hydroxybenzaldehyde intervention in a rat model of transient focal cerebral ischemia.

Gastrodiaelata Blume has been widely used to treat various central and peripheral nerve diseases, and Para‑hydroxybenzaldehyde (PHBA) is one of the indicated components suggested to provide a neuroprotective effect. In our previous, it was shown that PHBA protected mitochondria against cerebral ischemia‑reperfusion (I/R) injury in rats. In the present study, how PHBA regulated the metabolic mechanism in blood following cerebral I/R was assessed to identify an effective therapeutic target for the prevention and treatment of ischemic stroke (IS). First, a rat model of cerebral ischemia‑reperfusion injury was established via middle cerebral artery occlusion/reperfusion (MCAO/R). The therapeutic effect of PHBA on brain I/R was evaluated by assessing the neurological function score, triphenyl tetrazolium chloride, hematoxylin and eosin, and Nissl staining. Next, a non‑targeted metabolomic based on high‑performance liquid chromatography quadrupole time‑of‑flight mass spectrometry was established to identify differential metabolites. Finally, a targeted metabolic spectrum was analyzed and the potential therapeutic targets were verified by Western blotting. The results showed that the neurological function score, cerebral infarction area, hippocampal morphology, and the number of neurons in the PHBA group were significantly improved compared with the model group. Metabonomic analysis showed that 13 different metabolites were identified between the model and PHBA group, which may be involved in the 'tricarboxylic acid cycle', 'glutathione metabolism', and 'mutual transformation of pentose and glucuronates', amongst others. Among these, the levels of the most significant differential metabolite, dGMP, decreased significantly following PHBA treatment. Western blotting was used to verify the expression of membrane‑associated guanosine kinase PSD‑95 and the subunit of glutamate AMPA receptor GluA1, which significantly increased after PHBA treatment. In addition, it was also found that PHBA increased the expression of the light chain‑3 protein and autophagy effector protein 1, whilst the expression of sequestosome‑1 decreased, indicating that PHBA promoted autophagy. Similarly, in TUNEL staining and detection of apoptosis‑related proteins, it was found that MCAO/R upregulated the expression of Bax and cleaved‑caspase‑3 whilst downregulating the expression of Bcl‑2 and increasing the apoptosis of hippocampal neurons; PHBA reversed this situation. These results suggest that cerebral I/R causes postsynaptic dysfunction by disrupting the interaction between PSD‑95 and AMPARs, and the inhibition of the autophagy system eventually leads to the apoptosis of hippocampal neurons.