Chronic low back pain (LBP) has high prevalence in the adult population which is associated with enormous disability. Hence, our aim was to further characterise our LBP rat model by using immunohistological and immunohistochemical methods at an advanced stage (day 49) of the model. Male Sprague-Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but no discs were punctured. For LBP- but not sham-rats, noxious pressure hyperalgesia was fully developed in the lumbar axial deep tissues on day 21 post-surgery, which was maintained until at least day 49. In the lumbar (L4-L6) dorsal root ganglia (DRGs), somatostatin (SRIF) and the somatostatin receptor type 4 (SST receptor) were co-localised with substance P and IB4, markers of small diameter unmyelinated peptidergic and non-peptidergic C-fibres respectively as well as with NF200, a marker of medium to large diameter neurons. On day 49, there was increased expression of SRIF but not the somatostatin receptor type 4 (SST receptor) in the lumbar DRGs and the spinal dorsal horns. There were increased DRG expression levels of the putative pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK (pp44/pp42 MAPK) as well as pp38 MAPK expression levels in the lumbar spinal cord. Taken together, the increased expression of SRIF in the lumbar DRGs and spinal cord and its co-localisation with nociceptive fibres in DRG sections suggest a potential role of SRIF in modulating chronic mechanical LBP.
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http://dx.doi.org/10.1111/1440-1681.13402 | DOI Listing |
Alzheimers Dement
December 2024
MRC Protein Phosphorylation and Ubiquitylation Unit, Dundee, Scotland, United Kingdom.
Background: Accumulation of misfolded a-synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of synucleinopathies, which include Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). Therefore, clearance of misfolded α-synuclein from dopaminergic neurons could in principle offer a an approach for modifying synucleinopathies, which currently remain untreatable.
Method: In this study, we employ the Affinity-directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2-E3 ligase complex VHL and a nanobody selectively recognising the human α-synuclein protein RESULT: We demonstrate targeted degradation of endogenous α-synuclein from human cell lines with exquisite selectivity.
Background: We have previously reported the neuroprotective effects of fosgonimeton in amyloid-β (Aβ)-driven preclinical models of Alzheimer's disease (AD). Fosgonimeton is an investigational small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild-to-moderate AD (LIFT-AD; NCT04488419). Given the recent approvals of Aβ-targeting monoclonal antibodies (Aβ-mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ-mAbs.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
National Institute on Aging, NIH, Baltimore, MD, USA.
Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson's disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP-4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer's disease (AD) clinical trials. DPP-4Is are yet to be evaluated in PD or AD human studies.
View Article and Find Full Text PDFBackground: Accumulating evidence highlights impairment of autophagy as a key pathological feature of neurodegenerative diseases including Alzheimer's disease (AD). Autophagy is a highly dynamic, lysosome-based degradation process that promotes the clearance of degenerative factors to maintain cellular functions, preserve metabolic integrity, and ensure survival. Impaired autophagic function leads to the abnormal accumulation of autophagic vesicles (i.
View Article and Find Full Text PDFBackground: Alzheimer's disease (AD) is a neurodegenerative disorder without a cure. Targeting this multifactorial disease by repurposing FDA approved drugs serves as a faster mode of treatment due to its pre-established human safety. We tested terazosin (TZ), an a-1 adrenergic receptor (AR) antagonist and phosphoglycerate kinase-1 (PGK1) activator as having potential to treat AD.
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