Angélica González-Maciel

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.

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.

Introduction: Serotonin plays a critical role in pain modulation, making it a significant target for understanding and managing pain. Analyzing the most impactful publications can provide valuable insights into the intellectual structure, key contributors, and collaborative networks that have shaped the current state of knowledge in this field. Methods: A systematic review and bibliometric analysis were conducted using the Scopus database, identifying 856 articles related to serotonin-mediated pain modulation. After applying the inclusion criteria, the top 100 most-cited articles published between 1999 and 2021 were selected, representing a total of 33,500 citations. Citation metrics, publication years, authorship, institutions, countries, and journals were analyzed. Additionally, co-citation, keyword co-occurrence, and collaboration network analyses were performed to map the intellectual structure and collaborative patterns within the field. Results: The United States led contributions with 28% of publications, followed by France (15%) and Japan (12%). The 100 most-cited articles appeared across 45 journals, predominantly in Pain (15 articles) and Neuroscience (10 articles). Five major author clusters were identified, with key figures such as Hamon M., Yaksh T.L., and Porreca F. collectively accounting for over 5,000 citations. Four thematic keyword clusters, including “serotonin receptors,” “analgesia,” and “nociception,” were identified. International collaborations accounted for 65% of the publications. Discussion: The findings highlight the global and interdisciplinary nature of research on serotoninmediated pain modulation. Prominent research hubs, key contributors, and collaborative international networks have significantly shaped the field’s development. The identified trends and thematic areas provide valuable insight into the evolving landscape of neuropharmacology and pain research. Conclusion: This systematic review and bibliometric analysis provide a comprehensive overview of serotonin-mediated pain modulation research, emphasizing the importance of international collaboration and offering direction for future investigations into therapeutic strategies targeting serotonergic mechanisms in pain management.

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.

The emergence of clinical resistance to conventional antigiardials underscores the need for compounds with novel mechanisms of action. This study demonstrates that indirubin exerts antigiardial activity by targeting important metabolic enzymes in Giardia lamblia. Indirubin induced a concentration-dependent decrease in trophozoite proliferation and viability, correlating with reduced activity of native triosephosphate isomerase and aldose reductase. Using recombinant enzymes, indirubin directly inhibited triosephosphate isomerase and aldose reductase, with the parasite enzymes showing greater susceptibility than their human orthologs. Structural and computational analyses suggest preferential binding of indirubin at the dimer interface of triosephosphate isomerase and within the NADP(H)-binding pocket of aldose reductase. The dual enzymatic inhibition was concordant with methylglyoxal accumulation, extensive protein carbonylation, and the formation of advanced glycation end products. These effects culminated in apoptotic-like death and severe ultrastructural damage, including alteration of the adhesive disc and microtubule networks. By targeting vulnerabilities in the metabolic and redox pathways of G. lamblia through a multifactorial mechanism distinct from current therapies, our findings support indirubin as a promising candidate for the treatment of giardiasis.

Up to date, the pharmacological treatment for active neurocysticercosis (NCC) includes only two drugs, praziquantel and albendazole; however, the clinical response is not always successful, due to its low bioavailability; therefore, new approaches are needed. The aim of the present study was to evaluate the pharmacological interaction between praziquantel (PZQ) and oxfendazole (OXF) in vitro ; also, the drug-drug interaction between PZQ and OXF or fenbendazole (FBZ) in vivo using Taenia crassiceps metacestode was assessed. For the in vitro study, the surface of synergistic interaction (SSI) analysis was used to determine the kind of drug interaction between PZQ and OXF. Additionally, morphological and ultrastructural effects were investigated using transmission scanning electron microscopy. For the in vivo study, different doses of PZQ and FBZ or OXF were combined, and the cysticidal effect was determined. In vitro, results showed that 12 combinations exhibited synergism, and four exhibited additive effects. The 1:5 ratio of PZQ and OXF exhibited the highest synergistic effect, with an 11-fold increase in comparison to their theoretical sum. Microscopic observations revealed damage to the tegument and germinal layer; microtriches, flame cells, and muscular fibers were also affected. In vivo, results showed that PZQ + FBZ and PZQ + OXF (ratios 1:4 and 1:1, respectively) exhibited a synergistic reduction of the parasites. The findings of the present study show the potential of these combinations as a pharmacological alternative for cysticercosis treatment. Complementary studies are needed to determine their benefits in the clinical field.

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.

Billions of people are exposed to fine particulate matter (PM_2.5) levels above the USEPA’s annual standard of 9 μg/m³. Common emission sources are anthropogenic, producing complex aerosolized toxins. Ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs) have major detrimental effects on the brain, but the USA does not measure UFPM on a routine basis. This review focuses on the development and progression of common neurodegenerative diseases, as diagnosed through neuropathology, among young residents in Metropolitan Mexico City (MMC). MMC is one of the most polluted megacities in the world, with a population of 22 million residents, many of whom are unaware of the brain effects caused by their polluted atmosphere. Fatal neurodegenerative diseases (such as Alzheimer’s and Parkinson’s) that begin in childhood in populations living in air polluted environments are preventable. We conclude that UFPM/NPs are capable of disrupting neural homeostasis and give rise to relentless neurodegenerative processes throughout the entire life of the highly exposed population in MMC. The paradigm of reaching old age to have neurodegeneration is no longer supported. Neurodegenerative changes start early in pediatric ages and are irreversible. It is time to invest in preventive medicine.

Fibromyalgia (FM) is a disorder characterized by widespread chronic pain, significant depression, and various neural abnormalities. Recent research suggests a reciprocal exacerbation mechanism between chronic pain and depression. In patients with FM, dysregulation of tryptophan (Trp) metabolism has been identified. Trp, an essential amino acid, serves as a precursor to serotonin (5-HT), a neuromodulator that influences mood, appetite, sleep, and pain perception through the receptors 5-HT1, 5-HT2, and 5-HT3. Additionally, Trp is involved in the kynurenine pathway, a critical route in the immune response, inflammation, and production of neuroactive substances and nicotinamide adenine dinucleotide (NAD+). The activation of this pathway by pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ), leads to the production of kynurenic acid (KYNA), which has neuroprotective properties, and quinolinic acid (QA), which is neurotoxic. These findings underscore the crucial balance between Trp metabolism, 5-HT, and kynurenine, where an imbalance can contribute to the dual burden of pain and depression in patients with FM. This review proposes a novel therapeutic approach for FM pain management, focusing on inhibiting QA synthesis while co-administering selective serotonin reuptake inhibitors to potentially increase KYNA levels, thus dampening pain perception and improving patient outcomes.