Hung-Chuan Pan

Neuropathic pain is a debilitating condition lacking objective and quantitative assessment tools, as current evaluations rely largely on subjective reports. Hyperspectral imaging (HSI) is a non-invasive technology that quantifies spatial and spectral tissue characteristics and has been applied in rheumatologic and metabolic disorders. This study investigated whether HSI-detected paw skin alterations correlate with graded nerve injury severity in a chronic constriction injury (CCI) model. Sprague–Dawley rats were assigned to sham or CCI groups with one to four sciatic nerve ligatures. Behavioral assessments (CatWalk XT gait analysis, thermal hyperalgesia, and mechanical allodynia) and paw HSI measurements were performed longitudinally. Histological and molecular analyses were conducted from paw skin to dorsal spinal cord tissues. At 1100 nm, HSI demonstrated progressive and significant spectral deviations proportional to injury severity across all CCI groups, whereas 1300 nm changes were only detected in severe injuries. Histology revealed increased fibrosis, NGF, TNF-α, synaptophysin, and microglial activation with greater injury severity, alongside reduced PGP9.5, neurofilament, AChR, Desmin, GAP-43, Pax3, and BDNF expression. These molecular findings were supported by electrophysiological and behavioral impairments, which correlated with injury grade by HSI. In conclusion, HSI at 1100 nm provides a sensitive and objective indicator of neuropathic pain severity and holds promise as a quantitative translational tool.

Surgical outcomes are typically poor for patients with spontaneous large intracerebral hemorrhage (ICH) complicated by intraventricular hemorrhage (IVH). T

Open posterior lumbar surgery involves detaching paraspinal muscles from the spine to decompress neural tissues and to place instruments. While this operation improves the quality of life, it often has adverse effects on skeletal muscles like inflammation, degeneration, and fibrosis. Corticosteroids are well known for their anti-inflammatory function. In this study, we assessed the protective effects of intramuscular injection of corticosteroid on injured paraspinal muscles following surgery on the spine. C2C12 cells were co-exposed to hypoxia and lipopolysaccharide (LPS) to simulate ischemia and inflammatory response after muscle retraction to assess the effect of steroid. In vivo experiment, animals first underwent paraspinous muscle splitting with retractors to induce muscle injury, and later were assessed for neurobehavior, electrophysiology, and protein level related to inflammatory or regeneration following intramuscular (IM) steroid injection. Steroid rescued reduced cell viability caused by hypoxia + LPS, and attenuated induced protein expression of iNOS, COX2, Bad, and Bax. In neurobehavioral assessments (CatWalk, Ethovision, Von Frey test, and open field locomotor), retraction of paraspinous muscles worsened behaviors that were improved by IM steroid injections. The electrophysiology study showed that IM steroid injection lessened the muscle denervation caused by retraction. Similarly, IM steroid injections also attenuated dorsal root ganglion antigenicity of CGRP, Iba-1, and CD68 induced by muscle retraction. Muscle retraction downregulated AChR, desmin, PSD 95, and GAP 43, whereas IM steroid injection attenuated the adverse effects. The restoration of muscle morphology and decreased fibrosis were also facilitated by IM dexamethasone. IM steroid injection appears to protect against retraction damage in paraspinous muscle following spinal surgery. IM steroid paraspinous muscle injection may provide beneficial effects in spinal operations.

Background and Objectives: Pediatric cerebral arteriovenous malformations (AVMs) are associated with significant morbidity and mortality. The aim of this study was to assess the long-term outcomes of surgical excision and stereotactic radiosurgery (SRS) of cerebral AVMs in pediatric patients. Materials and Methods: A single-center retrospective analysis was conducted using data obtained from a single medical center between January 2012 and July 2022. The Modified Rankin Scale (mRS) at admission and discharge and the Spetzler–Martin (SM) scores were analyzed. Results: Among 45 patients (mean age 11.8 years), 19 patients (42.2%) received surgical resection, with good outcomes (mRS 0–2) in 16 patients and complete obliteration in all patients. In total, 26 patients (57.8%) were managed with SRS. After 36.3 months on average, complete obliteration in 19 of 26 patients (69.2%) was confirmed. Among the 7 SRS patients without complete obliteration, 6 had residual cerebral AVMs at the last follow-up, and 1 had recurrence. All patients receiving SRS had favorable outcomes (mRS 0–1) and no apparent radiosurgery-related complications. Conclusions: In our study, the surgical resection or SRS was selected based on individual patient conditions, and the overall outcomes were satisfactory. Both surgical resection and SRS proved to be effective treatment options. Microsurgical resection demonstrated a high rate of obliteration and remains a favorable therapeutic choice with acceptable risks for pediatric AVMs.

Microglia-mediated neuroinflammation is central to many neurological disorders. The Aryl hydrocarbon receptor (AhR) is highly expressed in microglia and plays a key role in neuroinflammation. While melatonin has anti-inflammatory effects in neurodegenerative disorders, its connection to AhR in modulating neuroinflammation is unclear. This study found that melatonin inhibits NF-κB activity, reduces pro-inflammatory mediators, and promotes an M2 microglia profile. Melatonin also enhances phospho-AhR (Tyr239) activation, increases Nrf2 expression, and decreases LPS-induced ROS generation in microglia. Melatonin's effects are similar to those achieved by AhR activation. In contrast, AhR knockout worsens neurological deficits and microglial activation, while melatonin reverses these effects by restoring AhR expression. In conclusion, effects of melatonin on microglia-mediated neuroinflammation are closely linked to phospho-AhR (Tyr239) activation and its associated downstream gene, Nrf2, via the AhR/Nrf2/ARE pathway. Therefore, melatonin, in conjunction with AhR may offer promising therapeutic benefits in neuroinflammatory disorders.

The treatment of large arteriovenous malformations (AVMs), in particular those unruptured, remains a topic of debate. Stereotactic radiosurgery has favorable outcomes for small to medium-sized AVMs. However, for large AVMs, the goal is to maximize obliteration rates and at the same time, to minimize radiation-induced complications. This study assessed outcomes of large symptomatic AVMs treated with Gamma Knife radiosurgery (GKRS) focusing on cases presenting with rupture or seizures. The study followed the guidelines of Taiwan Neurosurgical Consensus, a government-funded committee under the Central Bureau of Health Insurance that determines whether radiosurgery is an appropriate treatment. This retrospective study included 75 cases of large AVMs (> 10 cc) treated with GKRS during the period from June 2003 to January 2020. Inclusion criteria were as follows: a history of intracerebral hemorrhage (ICH) or seizures, no prior embolization, and periodic MRI examinations with clinical assessments post-GKRS. Treatment procedures were adapted based on the Taiwan Neurosurgical Consensus guidelines. The average patient age was 36.4 ± 16.1 years, with a median follow-up duration of 104 (range 82–150) months. Forty-six patients (61.3%) underwent single-stage treatment, while 29 patients (38.7%) received two-stage treatment. The mean AVM volume was 20.5 ± 11.7 cc, with an average peripheral radiation dose of 17.7 ± 1.2 Gy. Among the 32 cases with AVM volumes between 10 and 15 cc, 25 (78.1%) achieved total obliteration. For the 17 cases with volumes between 15 and 20 cc, 7 (41.2%) achieved total obliteration, while 8 out of 26 (30.8%) cases with volumes > 20 cc achieved total obliteration. Severe brain edema developed in 16 patients (21.3%) after an average follow-up of 105.4 ± 56.2 months, but 11 patients (14.6%) experienced symptoms. Only one patient (1.3%) suffered neurological disability. Seizure control in Engel classification I was achieved in 21 of 42 patients (50%). Eight patients (10.6%) experienced new hemorrhages, with 4 (12.1%) occurring in those with a prior history of hemorrhage (annual bleeding rate: 1.2%) and 4 (9.5%) in those patients with a history of seizures (annual bleeding rate: 1.1%). Univariate analyses showed that total obliteration was significantly associated with smaller nidus volumes (< 15 cc), single-stage radiosurgery, Radiosurgery-Based Grading Scale, first-stage volume, maximum dose, 12 Gy volume, and nidus coverage percentages at 16 Gy and 18 Gy. Multivariate analyses revealed that post-GKRS symptoms and severe brain edema were significantly correlated with the following: Virginia Radiosurgery AVM Score, Charlson Comorbidity Index, and mean radiation dose. The obliteration rate of large AVMs is strongly correlated with their size. This approach appears to achieve the goals of obliteration and minimizing the risks of radiation-induced complications and hemorrhage. Further investigation is needed for adjuvant treatments in residual or refractory cases after GKRS.

Activation of Sirtuin 1 (SIRT-1) is vital for axonogenesis and nerve regeneration. Caloric restriction (CR) has health benefits and protects against neurodegenerative disorders, largely through SIRT-1 regulation. This study investigates how diet control impacts peripheral nerve injury, focusing on SIRT-1 expression. We prepared nerve tissue cultures for a pharmacological analysis of SIRT-1's effects on nerve degeneration. After two weeks of 70% caloric restriction, we crushed the left sciatic nerve of Sprague–Dawley rats with a vessel clamp. We then administered SIRT-1 agonists or antagonists intraperitoneally. Nerve explant cultures showed increased SIRT-1 expression with SRT-1720, which was reduced by EX527, indicating enhanced regeneration. In the animal study, diet control led to notable SIRT-1 expression in plasma. This expression increased with SIRT-1 agonists and decreased with antagonists. SIRT-1 levels in paw skin were strongly correlated with PGP 9.5 and collagen deposition, while nerve fiber size and regeneration markers (S-100 and NF) also correlated with SIRT-1 expression. Inflammatory markers showed an inverse relationship with SIRT-1. TNF-α and NGF in the dorsal root ganglion responded reciprocally to SIRT-1 expression. Increased acetylcholine receptors and desmin in denervated muscle were parallel to SIRT-1 levels, with similar trends observed in muscle weight and diameter. Neurobehavioral and electrophysiological results aligned with these measurements. Caloric restriction has a preventative effect on nerve damage, mainly through SIRT-1 modulation. From a health perspective, promoting caloric restriction is important for mitigating nerve injury severity.

Microglial cells are a macrophage-like cell type residing within the CNS. These cells evoke pro-inflammatory responses following thrombin-induced brain damage. Inflammasomes, which are large caspase-1-activating protein complexes, play a critical role in mediating the extracellular release of HMGB1 in activated immune cells. The exact role of inflammasomes in microglia activated by thrombin remains unclear, particularly as it relates to the downstream functions of HMGB1. After receiving microinjections of thrombin, Sprague Dawley rats of 200 to 250 gm were studied in terms of behaviors and immunohistochemical staining. Primary culture of microglia cells and BV-2 cells were used for the assessment of signal pathways. In a water maze test and novel object recognition analysis, microinjections of thrombin impaired rats’ short-term and long-term memory, and such detrimental effects were alleviated by injecting anti-HMGB-1 antibodies. After thrombin microinjections, the increased oxidative stress of neurons was aggravated by HMGB1 injections but attenuated by anti-HMGB-1 antibodies. Such responses occurred in parallel with the volume of activated microglia cells, as well as their expressions of HMGB-1, IL-1β, IL-18, and caspase-I. In primary microglia cells and BV-2 cell lines, thrombin also induced NO release and mRNA expressions of iNOS, IL-1β, IL-18, and activated caspase-I. HMGB-1 aggravated these responses, which were abolished by anti-HMGB-1 antibodies. In conclusion, thrombin induced microglia activation through triggering inflammasomes to release HMGB1, contributing to neuronal death. Such an action was counteracted by the anti-HMGB-1 antibodies. The refinement of HMGB-1 modulated the neuro-inflammatory response, which was attenuated in thrombin-associated neurodegenerative disorder.

Thrombin is a multifunctional serine protein which is closely related to neurodegenerative disorders. The Aryl hydrocarbon receptor (AhR) is well expressed in microglia cells involving inflammatory disorders of the brain. However, it remains unclear as to how modulation of AhR expression by thrombin is related to the development of neurodegeneration disorders. In this study, we investigated the role of AhR in the development of thrombin-induced neurodegenerative processes, especially those concerning microglia. The primary culture of either wild type or AhR deleted microglia, as well as BV-2 cell lines, was used for an in vitro study. Hippocampal slice culture and animals with either wild type or with AhR deleted were used for the ex vivo and in vivo studies. Simulations of ligand protein docking showed a strong integration between the thrombin and AhR. In thrombin-triggered microglia cells, deleting AhR escalated both the NO release and iNOS expression. Such effects were abolished by the administration of the AhR agonist. In thrombin-activated microglia cells, downregulating AhR increased the following: vascular permeability, pro-inflammatory genetic expression, MMP-9 activity, and the ratio of M1/M2 phenotype. In the in vivo study, thrombin induced the activation of microglia and their volume, thereby contributing to the deterioration of neurobehavior. Deleting AhR furthermore aggravated the response in terms of impaired neurobehavior, increasing brain edema, aggregating microglia, and increasing neuronal death. In conclusion, thrombin caused the activation of microglia through increased vessel permeability, expression of inflammatory response, and phenotype of M1 microglia, as well the MMP activity. Deleting AhR augmented the above detrimental effects. These findings indicate that the modulation of AhR is essential for the regulation of thrombin-induced brain damages and that the AhR agonist may harbor the potentially therapeutic effect in thrombin-induced neurodegenerative disorder.