Air pollution plays a key role in sleep disorders and neurodegeneration. Alzheimer’s disease (AD), Parkinson’s disease (PD), and/or transactive response DNA-binding protein TDP-43 neuropathology have been documented in children and young adult forensic autopsies in the metropolitan area of Mexico City (MMC), along with sleep disorders, cognitive deficits, and MRI brain atrophy in seemingly healthy young populations. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) reach urbanites’ brains through nasal/olfactory, lung, gastrointestinal tract, and placental barriers. We documented Fe UFPM/NPs in neurovascular units, as well as lateral hypothalamic nucleus orexinergic neurons, thalamus, medullary, pontine, and mesencephalic reticular formation, and in pinealocytes. We quantified ferromagnetic materials in sleep and arousal brain hubs and examined their motion behavior to low magnetic fields in MMC brain autopsy samples from nine children and 25 adults with AD, PD, and TDP-43 neuropathology. Saturated isothermal remanent magnetization curves at 50–300 mT were associated with UFPM/NP accumulation in sleep/awake hubs and their motion associated with 30–50 µT (DC magnetic fields) exposure. Brain samples exposed to anthropogenic PM pollution were found to be sensitive to low magnetic fields, with motion behaviors that were potentially linked to the early development and progression of fatal neurodegenerative diseases and sleep disorders. Single-domain magnetic UFPM/NPs in the orexin system, as well as arousal, sleep, and autonomic regions, are key to neurodegeneration, behavioral and cognitive impairment, and sleep disorders. We need to identify children at higher risk and monitor environmental UFPM and NP emissions and exposures to magnetic fields. Ubiquitous ferrimagnetic particles and low magnetic field exposures are a threat to global brain health.

Background: Pain is a frequent and debilitating non-motor symptom of Parkinson’s disease; however, its central neurochemical mechanisms remain incompletely understood. Serotonin modulates nociceptive processing, and the 5-HT3A receptor has been implicated in excitatory signaling and central sensitization. However, thalamic Htr3a transcript regulation during persistent pain associated with dopaminergic injury remains unclear. Objective: To evaluate thalamic Htr3a mRNA expression in 6-OHDA hemi-Parkinsonian rats subjected to formalin-induced persistent pain. Methods: Male Wistar rats were assigned to six groups (n = 6/group): Saline, Formalin, SHAM + Saline, SHAM + Formalin, 6-OHDA + Saline, and 6-OHDA + Formalin. 6-OHDA lesions were validated via apomorphine-induced rotations (>7 turns/min). Nociceptive behavior (flinches) was recorded over 60 min post-formalin injection. Bilateral thalamic Htr3a mRNA expression was quantified by RT-qPCR using Rpl27 as a validated reference gene. Results: 6-OHDA + Formalin rats exhibited a significant increase in persistent-phase nociceptive behavior compared to controls (p < 0.05). Htr3a mRNA expression showed a significant bilateral reduction in 6-OHDA-lesioned rats compared to controls (p < 0.05), with the decrease being significantly more severe in the ipsilateral thalamus (p < 0.001). Conclusions: Unilateral 6-OHDA lesion is associated with a region-dependent reduction in thalamic Htr3a mRNA expression during persistent pain. These results demonstrate transcriptional adaptations of the thalamic serotonergic system in experimental parkinsonian persistent pain.

Background: Pain is one of the most common and disabling non-motor symptoms of Parkinson’s disease; however, the neurochemical mechanisms that modulate it remain incompletely understood. Serotonin plays an active role in central nociceptive processing, and the 5-HT3A receptor has been linked to excitatory pain transmission and central sensitization. However, its role in the thalamus during persistent pain associated with dopaminergic neurodegeneration remains unclear. Objective: This study aimed to evaluate the Htr3a gene expression in the thalamus of hemi-Parkinsonian rats subjected to a model of persistent formalin-induced pain. Methods: Male Wistar rats were divided into six experimental groups: saline solution, formalin, SHAM + saline solution, SHAM + formalin, 6-hydroxydopamine (6-OHDA) lesion + saline solution, and 6-OHDA + formalin. We assessed nociceptive behavior by counting withdrawals during the 60 minutes following formalin administration. We then performed bilateral thalamic dissection and quantified Htr3a gene expression by real-time PCR using Rpl27 as an endogenous reference gene. Results: Rats in the 6-OHDA + formalin group showed a significant increase in nociceptive behavior during the persistent phase of the formalin test compared with the control and SHAM groups (p < 0.05). Similarly, rats with 6-OHDA lesions showed a significant decrease of approximately 78% in relative Htr3a gene expression in the thalamus compared with the control group (p < 0.05). Conclusions: These findings suggest that dopaminergic neurodegeneration is associated with altered Htr3a gene expression in the thalamus and support the possible involvement of serotonergic mechanisms in processing persistent pain in Parkinson’s disease.

Background: Treatment-resistant depression (TRD) represents a major clinical challenge and is increasingly associated with persistent neuroinflammatory processes. Evidence suggests that dysregulation of the immune system, particularly the imbalance between pro-inflammatory and anti-inflammatory cytokines, contributes to poor therapeutic response. In this context, interleukin-10 (IL-10) has emerged as a key mediator in regulating the inflammatory response. Objective: To systematically analyze the evidence on neuroimmune dysregulation in depression, with an emphasis on TRD, and to evaluate the potential role of IL-10 as a biomarker and modulator of therapeutic response. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Fourteen studies were included, comprising randomized clinical trials, longitudinal studies, a prospective cohort study, and exploratory designs. Methodological quality was assessed using the RoB 2 tool and complementary approaches. Data were integrated through a qualitative analysis focused on inflammatory biomarkers and clinical outcomes. Results: The studies consistently showed an association between elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and the severity of depressive symptoms, as well as reduced response to conventional treatments. Immunomodulatory interventions, including ketamine, pentoxifylline, and minocycline, were associated with clinical improvement, particularly in patients with elevated baseline inflammation. IL-10 appears to be involved in counter-regulatory neuroimmune processes associated with inflammatory balance. Conclusions: Neuroinflammation plays a central role in TRD. IL-10 may serve as a relevant biomarker and a potential target for personalized therapeutic strategies informed by immune profiles, through modulation of neuroinflammatory pathways.

Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson’s disease (26.9%), two Alzheimer’s disease-related models (7.7%), and one Huntington’s disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer’s disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.