Biology subjects

De Felice, M.

Publications and source records attributed to De Felice, M..

4 recordsLinked to original sources

bioRxiv2026

Dual MMP-9/12 Inhibition with AZD1236 Confers Neurovascular Protection and Reduces Post-Stroke Pain in Experimental Stroke Models.

Background: Stroke remains a leading cause of death and disability worldwide. Matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-12, contribute to early blood-brain barrier (BBB) disruption, neuroinflammation, haemorrhagic transformation, and intracerebral haemorrhage (ICH). Intravenous thrombolysis is the only widely used pharmacological therapy for acute ischaemic stroke, but its utility is limited by narrow eligibility criteria and haemorrhagic risk. Inhibition of MMPs in the acute phase may offer a complementary neurovascular protective strategy. Methods: AZD1236, a selective dual MMP-9/-12 inhibitor, was evaluated in transient and permanent middle cerebral artery occlusion models and in a collagenase-induced ICH model in young, aged, obese, and female mice. Drug or vehicle was administered 2-6 hours after stroke onset. Outcomes included infarct or haematoma volume, BBB integrity, neurological function, and pain-related behaviours. Results: AZD1236 given within 2-4 hours after ischaemic or haemorrhagic insult significantly reduced infarct and haematoma volumes, improved short- and long-term neurological scores, and preserved BBB integrity, whereas treatment at 6 hours was largely ineffective. AZD1236 also attenuated the development of post-stroke mechanical allodynia and thermal hyperalgesia. Mechanistically, treatment reduced MMP-9 and MMP-12 activity, increased tight junction protein expression, and dampened inflammatory responses. Conclusions: Dual inhibition of MMP-9/-12 with AZD1236 confers robust neurovascular protection and mitigates post-stroke pain across clinically relevant models of ischaemic and haemorrhagic stroke. These findings provide a strong preclinical rationale for clinical evaluation of dual MMP-9/12 inhibition as an adjunctive neuroprotective strategy for acute stroke.

neuroscience↗

bioRxiv2026

Continuous sumatriptan exposure induces persistent trigeminovascular sensitisation and brain perfusion changes in a rat model of medication overuse headache.

BackgroundRepeated exposure to acute antimigraine medication can promote medication overuse headache, but the mechanisms underlying this transition remain incompletely understood. We used a clinically relevant rat model of continuous sumatriptan exposure to investigate whether medication overuse is associated with persistent sensitisation of the trigeminovascular system and longer-lasting changes in brain perfusion. MethodsAdult male Sprague Dawley rats received continuous subcutaneous sumatriptan (0.6 mg/kg/day) or saline infusion for 6 days via osmotic minipumps. Periorbital and hindpaw mechanical thresholds were measured over 20 days. On day 6 and day 20, trigeminal ganglia and trigeminal nucleus caudalis were processed for immunohistochemistry for pERK, pp38, Iba-1, GFAP and NeuN. On day 20, a subgroup received sodium nitroprusside (SNP, 3 mg/kg, i.p.) to unmask latent sensitisation. Cerebral blood flow was assessed by MRI. ResultsSumatriptan induced reversible cephalic and extracephalic allodynia. Previously exposed rats showed evidence of persistent sensitisation, including enhanced biomarker and glial responses after withdrawal and following SNP challenge. pERK and pp38 expression increased in both the trigeminal ganglion and trigeminal nucleus caudalis. In the TNC, marker association shifted over time from predominantly neuronal at day 6 to greater apparent glial association at day 20. Iba-1 and GFAP expression increased after withdrawal of sumatriptan and was further enhanced by SNP challenge. Within the TNC, neuronal marker expression was greatest in the ophthalmic representation. Sumatriptan exposure also produced a persistent reduction in cerebral blood flow that remained evident after behavioural recovery. ConclusionContinuous sumatriptan exposure produces prolonged trigeminovascular neuronal and glial alterations together with persistent changes in brain perfusion. These data support a state of latent sensitisation after repeated triptan exposure and provide mechanistic insight into medication overuse headache. HIGHLIGHTSO_LIRepeated sumatriptan exposure induces reversible cephalic and extracephalic allodynia but leaves persistent trigeminovascular sensitisation after drug withdrawal. C_LIO_LIpERK and pp38 expression increase in the trigeminal ganglion and trigeminal nucleus caudalis, with the strongest regional changes seen in the ophthalmic representation of the TNC. C_LIO_LIDelayed increases in Iba-1 and GFAP in the TNC suggest that glial activation may contribute to maintenance of latent sensitisation, although the colocalisation findings are qualitative and should be interpreted cautiously. C_LIO_LIRepeated sumatriptan exposure is also associated with a persistent reduction in cerebral blood flow, indicating longer-lasting changes in brain perfusion beyond the period of overt allodynia. C_LI

neuroscience↗

bioRxiv2026

Resolving thyroid lineage cell trajectories merging into a dual endocrine gland in mammals

The thyroid has a remarkable evolution, first appearing in invertebrate chordates as an integral exocrine constituent of the pharyngeal endostyle that is transformed into an endocrine gland during metamorphosis in basal vertebrates. In mammals, the thyroid acquires a second endocrine cell type, calcitonin-producing C-cells, which for long were inferred a neural crest origin, shuttled to the embryonic thyroid by the ultimobranchial bodies. However, recent lineage tracing experiments firmly establish these neuroendocrine cells also derive from foregut endoderm. Key questions remaining unanswered are how thyroid primordia independently develop and, unlike in all non-mammalian vertebrates, merge into a dual endocrine organ. Here, by leveraging a single-cell transcriptome atlas derived from mouse pharyngeal endoderm and its subsequent cell fates, we characterize the global gene expression profile of thyroid- and ultimobranchial-derived progenitor cells and identify comprehensive gene regulatory networks of lineage-specific transcription factors and novel target genes predicted to differentially regulate cell proliferation, plasticity and differentiation during development. Spatiotemporal analyses reveal C-cell precursors are triggered to undergo epithelial-mesenchymal transition (EMT) and cell-autonomously down-regulate collagen IV and degrade laminin that delineates the ultimobranchial body epithelium. However, the EMT program is not fully deployed until both cell lineages are mixed and propagate conjointly thus forming the typical thyroid histoarchitecture of follicles and parafollicular C-cells, every follicle/C-cell unit being enveloped by a renewed basement membrane. Mixed-type thyroid carcinoma recapitulates a synchronous lineage growth pattern but only the neuroendocrine tumor cells are able to escape the compound follicle boundaries and become invasive adopting a C-cell precursor-like migratory phenotype.

developmental biology↗

bioRxiv2025

Intergenerational Conditioning via Intermittent Parental Hypoxia Confers Stroke Resilience in Offspring

Background and AimsIntergenerational disease transmission, where parental exposures or experiences influence disease susceptibility in offspring, may represent a crucial layer of stroke risk that extends beyond genetics alone. Environmental conditioning, such as intermittent sub-lethal hypoxia, can induce adaptive protective stress responses in the brain. However, whether such parental conditioning enhances offspring resilience to cerebral ischaemia remains unclear. This study investigates whether intermittent hypoxia in parents acts as an intergenerational conditioning stimulus, conferring resilience to ischaemic stroke in offspring, and explores associated molecular mechanisms. MethodsMale and female Balb/C mice (F0) were exposed to intermittent hypoxia (8% O2, 2 hours every other day, 16 cycles) prior to mating. To confirm that intermittent hypoxia induced neuroprotection in the parental generation, a separate cohort of F0 mice underwent transient middle cerebral artery occlusion (tMCAO). Offspring (F1) were generated from hypoxia-exposed F0 breeders and divided into four groups: biparental hypoxia, paternal hypoxia, maternal hypoxia, and normoxic controls. Adult F1 offspring also underwent tMCAO to model ischaemic stroke. Infarct volume and brain swelling were assessed 48 hours post-ischaemia. In a subgroup of F1 offspring, tandem mass tag (TMT)-based proteomic analysis of injured brain tissue was performed post-stroke to identify molecular pathways associated with neuroprotection. ResultsParental intermittent hypoxia significantly reduced infarct size and swelling in F0 mice. These protective effects were inherited by F1 offspring, with biparental exposure producing the greatest reduction in infarct volume, followed by maternal-only and paternal-only groups, and exhibiting sex-specific differences. Proteomic profiling revealed distinct treatment and lineage clusters. Key pathways implicated in offspring neuroprotection included metabolic regulation, immune signalling, cytoskeletal organisation, and cell survival, notably involving PI3K-Akt and EGFR pathways. ConclusionsIntermittent hypoxia in parents acts as an intergenerational conditioning stimulus, conferring offspring resilience to ischaemic stroke. This neuroprotective phenotype is supported by coordinated molecular adaptations in key pathways involved in survival and stress response. These findings highlight the potential for parental environmental conditioning to shape stroke outcomes in offspring, opening new avenues for therapeutic exploration.

neuroscience↗