Young Wook Yoon

Background: Spinal cord injury (SCI) leads to persistent inflammation, contributing to chronic neuropathic pain. However, current treatments show limited efficacy. Three types of nitric oxide synthase (NOS) play different roles in inflammation and neuronal hyperexcitation. Therefore, this study aimed to determine the predominant NOS subtype involved in neuropathic pain after spinal contusion. Methods: We investigated the effects of intrathecal NOS inhibitors on mechanical sensitivity following a moderate spinal contusion injury in male Sprague‐Dawley rats. These NOS inhibitors were N(G)‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME; non‐selective NOS inhibitor), 1400W (iNOS inhibitor), Nω‐propyl‐L‐arginine hydrochloride (NPLA; nNOS inhibitor) and N5‐(1‐iminoethyl)‐L‐ornithine (L‐NIO; eNOS inhibitor). Additionally, we analysed protein expression and cellular localisation of spinal NOS subtypes in rats that underwent SCI or sham procedures. Results: Treatment with L‐NAME significantly reduced paw withdrawal threshold in a dose‐dependent manner, although motor deficits appeared at the highest dose (30 μM), while 1400W effectively alleviated mechanical hypersensitivity without motor side effects. NPLA showed limited efficacy, and L‐NIO had no effect. Protein expression of iNOS increased two‐fold in the L4‐5 spinal segment of SCI rats compared with sham controls. After SCI, iNOS‐immunoreactivity colocalized with GFAP in the superficial laminae of the L4‐5 spinal segment. Treatment with 1400W reduced the hyper‐reactivity of both iNOS and GFAP. Conclusions: These findings indicate that iNOS plays a significant role in below‐level neuropathic pain following thoracic spinal cord contusion in rats. Specific blockade of iNOS activity may have potential as a therapeutic intervention for spinal‐contusion‐induced neuropathic pain with reduced risk of side effects. Significance Statement: iNOS inhibition effectively alleviated pain without motor side effects, unlike non‐selective NOS, nNOS and eNOS inhibitors. The colocalization of iNOS with astrocytes in the spinal cord suggests a key mechanism in pain maintenance. These findings highlight the potential of targeting iNOS as a therapeutic strategy for SCI‐induced neuropathic pain with reduced risks of side effects.

Traumatic spinal cord injury (SCI) causes secondary damage in injured and adjacent regions due to temporal deprivation of oxygen and energy supply. Peroxisome proliferator‐activated receptor γ (PPARγ) is known to regulate cell survival mechanisms such as hypoxia, oxidative stress, inflammation and energy homeostasis in various tissues. Thus, PPARγ has the potential to show neuroprotective properties. However, the role of endogenous spinal PPARγ in SCI is not well established. In this study, under isoflurane inhalation, a 10‐g rod was freely dropped onto the exposed spinal cord after T10 laminectomy using a New York University impactor in male Sprague–Dawley rats. Cellular localization of spinal PPARγ, locomotor function and mRNA levels of various genes including NFκB‐targeted pro‐inflammatory mediators after intrathecal administration of PPARγ antagonists, agonists or vehicles in SCI rats were then analysed. In both sham and SCI rats, spinal PPARγ was presented in neurons but not in microglia or astrocytes. Inhibition of PPARγ induced IκB activation and increased mRNA levels of pro‐inflammatory mediators. It also suppressed recovery of locomotor function with myelin‐related gene expression in SCI rats. However, a PPARγ agonist showed no beneficial effects on the locomotor performances of SCI rats, although it further increased the protein expression of PPARγ. In conclusion, endogenous PPARγ has a role in anti‐inflammation after SCI. Inhibition of PPARγ might have a negative influence on motor function recovery through accelerated neuroinflammation. Nonetheless, exogenous PPARγ activation does not appear to effectively help with functional improvement after SCI.

A substantial amount of amyloid-beta (Aβ) accumulates in the occipital cortices; however, it draws less attention. We investigated the clinical implications of Aβ accumulation in the occipital lobes in the Alzheimer’s disease (AD) continuum. [18F]-Florbetaben amyloid PET scans were performed in a total of 121 AD or amnestic mild cognitive impairment (aMCI) patients. Of the 121 patients, 74 Aβ positive patients were divided into occipital Aβ positive (OCC+) and occipital Aβ negative (OCC−) groups based on Aβ accumulation in the bilateral occipital lobes. The OCC+ group (41/74, 55.4%) was younger and had a younger age at onset than the OCC− group. The OCC+ group also had an increased standard uptake value ratio in the occipital lobes and greater cortical thinning in relevant areas. The OCC+ group had a higher global deterioration scale, lower performance for the copy, immediate recall, delayed recall, and recognition in Rey–Osterrieth Complex Figure tests than the OCC- group, although both groups had similar disease durations. AD or aMCI patients in the OCC+ group exhibited features noted in early onset AD with relevant neuropsychological and image findings. Occipital Aβ positivity in amyloid PET scans need to be considered as an underestimated marker of early onset AD continuum.

The most common type of spinal cord injury is the contusion of the spinal cord, which causes progressive secondary tissue degeneration. In this study, we applied genetically modified human neural stem cells overexpressing BDNF (brain-derived neurotrophic factor) (F3.BDNF) to determine whether they can promote functional recovery in the spinal cord injury (SCI) model in rats. We transplanted F3.BDNF cells via intrathecal catheter delivery after a contusion of the thoracic spinal cord and found that they were migrated toward the injured spinal cord area by MR imaging. Transplanted F3.BDNF cells expressed neural lineage markers, such as NeuN, MBP, and GFAP and were functionally connected to the host neurons. The F3.BDNF-transplanted rats exhibited significantly improved locomotor functions compared with the sham group. This functional recovery was accompanied by an increased volume of spared myelination and decreased area of cystic cavity in the F3.BDNF group. We also observed that the F3.BDNF-transplanted rats showed reduced numbers of Iba1- and iNOS-positive inflammatory cells as well as GFAP-positive astrocytes. These results strongly suggest the transplantation of F3.BDNF cells can modulate inflammatory cells and glia activation and also improve the hyperalgesia following SCI.

The recent advance of positron emission tomography (PET) tracers as biomarkers in Alzheimer’s disease (AD) provides more insight into pathophysiology, preclinical diagnosis, and further therapeutic strategies. However, synergistic processes or interactions between amyloid and tau deposits are still poorly understood. To better understand their relationship in focal brain changes with clinical phenotypes, we focused on region-specific or atypical AD characterized by focal clinical presentations: Posterior cortical atrophy (PCA) and logopenic variant of primary progressive aphasia (lpvPPA). We compared three different PET images with ¹⁸F–THK–5351 (tau), ¹⁸F–Florbetaben (amyloid beta, Aβ), and ¹⁸F–Fluorodeoxyglucose (glucose metabolism) to investigate potential interactions among pathologies and clinical findings. Whereas the amyloid accumulations were widespread throughout the neocortex, tau retentions and glucose hypometabolism showed focal changes corresponding to the clinical features. The distinctly localized patterns were more prominent in tau PET imaging. These findings suggest that tau pathology correlates more closely to the clinical symptoms and the neurodegenerative processes than Aβ pathology in AD.

Electric stimulation is used for managing osteoarthritic (OA) pain; however, little is known about the development of analgesic tolerance during repeated stimulations and the relation of spinal microglia with OA pain. We investigated the changes in the analgesic effects of repeated electric stimulations and the relation between the development of analgesic tolerance and spinal microglial expression in rats with OA. To induce OA, monosodium iodoacetate was injected into the synovial space of the right knee joint of the rats (n = 185). Repeated high frequency, low frequency, or sham transcutaneous electric nerve stimulation (TENS) was performed to the ipsilateral knee joint for 20 min in rats with OA (n = 45). Minocycline or minocycline plus TENS (HF, LF, or sham) was treated in OA rats with repeated TENS-induced tolerance (n = 135). Immunohistochemistry of the microglia in the L3–L5 spinal segments was performed. Knee joint pain during passive movement of the knee joint were quantified using the knee-bend score and the proportion of activated microglia was calculated as primary variables. Paw withdrawal threshold (hypersensitivity to mechanical stimuli) was assessed and the resting and activated microglia were counted as secondary variables. Repeated applications decreased the analgesic effect of TENS on OA pain and failed to reduce the expression of activated microglia in the spinal cord. However, spinal microglial inhibition by minocycline restored the analgesic effect of TENS on OA pain in TENS-tolerant OA rats. TENS combined with minocycline treatment improved knee joint pain and mechanical hypersensitivity in TENS-tolerant OA rats, and inhibited the expression of activated microglia in the spinal cord. These results suggest a possible relationship between repetitive electric stimulation-induced analgesic tolerance for OA pain control and changes in microglia activation.

Objectives: Peroxisome proliferator-activated receptors (PPARs) control wound healing processes in damaged tissues. PPAR agonists have neuroprotective effects in spinal cord injury (SCI); however, isotype-specific roles of PPARs are not well understood. Therefore, we evaluated protein expression changes for three isotypes of PPARs at different time points and locations relative to the epicenter after SCI in rats. Methods: A 10-g rod was dropped on the spinal cord which located at the T10 vertebra of rats from a height of 6.25, 12.5, or 50 mm using New York University impactor. We collected the spinal cord at 6, 12, 24, and 72 h and 1, 3, and 5 weeks after SCI. The protein expression of PPARs was analyzed using western blot. Results: The protein expression of PPAR-α declined gradually up to 5 weeks at the epicenter. PPAR-β/δ expression increased from 3 days to 5 weeks at the caudal region, but decreased at the epicenter in the severe injury group. PPAR-γ expression increased significantly at all regions in all three injury groups up to 5 weeks after SCI and increased to a greater extent in the severe injury group. In addition, PPAR-β/δ controlled protein expression of PPAR-α positively, and -γ negatively. Conclusions: The present results suggest that different PPAR isotypes have varied protein expression patterns at the epicenter and in adjacent regions after SCI. Our results suggest that PPARs may have overlapping but distinct roles. These findings will be useful for further studies investigating PPARs in neurological disorders including SCI.