IgG4-related disease (IgG4-RD) of the central nervous system (CNS) is a recently recognized entity, often misdiagnosed as neoplastic or inflammatory conditions. We present the largest retrospectively analysed Indian cohort of nine cases histologically diagnosed as CNS IgG4-RD from 2021 to 2024, integrating clinical, serological, pathological, treatment, radiological, and follow-up details. The mean age of the cohort was 25.9 ± 8.8 years (range: 11–41 years), with a male-to-female ratio of 2:1. Headache (5/9) and seizures (3/9) were the most common presentations, with lesions involving the frontal/frontotemporal dura (3/9), cerebellopontine angle (2/9), and tentorium (1/9), among others (3/9). Radiological impressions included hypertrophic pachymeningitis or inflammatory disease (4/9), meningioma (3/9), vestibular schwannoma (1/9), and IgG4-RD (1/9). Preoperative, serum IgG4 levels testing was done in 4/9 cases, and levels exceeded 1.35 g/L in 3/4 patients. Following the 2020 revised comprehensive diagnostic criteria for IgG4-RD, three cases were classified as definite and six as probable for IgG4-RD. Histopathological findings of dense lymphoplasmacytic infiltrates with storiform fibrosis, with >10 IgG4-positive plasma cells per high-power field and an IgG4/IgG-positive plasma-cell ratio >40
Cysteinyl leukotriene receptor 1 (CysLTR1) has been implicated in various inflammatory conditions; however, its role in Parkinson’s disease (PD) pathogenesis remains to be explored. This study elucidated the neuroprotective potential of montelukast pre-treatment in rotenone-exposed SH-SY5Y cells in vitro. Notably, montelukast effectively attenuated rotenone-induced upregulation of CysLTR1, suppressed the p38-MAPKAPK2 signalling axis, and reduced pro-inflammatory cytokines. mitigated oxidative stress cascades and restored antioxidant enzyme levels, including activation of the NRF2-KEAP1 axis. Furthermore, montelukast treatment restored dynamin-related protein 1 (DRP1) levels, preserved tyrosine hydroxylase (TH) and PARK7/DJ1 expression, and reduced α-synuclein accumulation in SH-SY5Y cells. Montelukast showed neuroprotective effects by alleviating oxidative stress, modulating the inflammatory response, and preserving key PD biomarkers against rotenone-induced cellular damage. The outcomes imply the potential for repurposing montelukast as a therapeutic option for PD. Clinical trial number: Not applicable.
Epilepsy is not merely a chronic neurological disorder characterized by recurrent, spontaneous seizures at the clinical level; rather, it represents a complex pathophysiological condition involving profound structural, functional, and molecular reorganization within neuronal networks. The marked heterogeneity of epilepsy arises from the multilayered interplay of genetic susceptibility, acquired brain insults such as trauma, ischemia, or infection, developmental abnormalities, and environmental factors. This multifactorial etiology poses substantial challenges for clinical management and limits the effectiveness of current therapeutic approaches, which are largely restricted to symptomatic seizure suppression. Experimental epilepsy models constitute indispensable tools for addressing these unmet clinical and scientific needs. Chemical, electrical, genetic, and acquired models enable systematic investigation of epilepsy across multiple biological scales, ranging from alterations in neuronal excitability and synaptic plasticity to neuroinflammatory processes and network-level synchronization disturbances. Beyond providing mechanistic insight, these models serve as essential platforms for preclinical evaluation of novel pharmacological agents and neuromodulation-based therapeutic strategies. The review encompasses a broad experimental spectrum, including chemoconvulsant models such as pentylenetetrazol, pilocarpine, and kainic acid; electrical stimulation paradigms; genetic and developmental models; and acquired epilepsy models. In addition, in vitro and ex vivo systems, outcome measures, and model optimization strategies for drug screening and therapeutic development are discussed. By highlighting the limitations of single-model approaches and emphasizing complementary experimental strategies, this review aims to advance a comprehensive understanding of epilepsy pathophysiology and support the development of more effective, mechanism-based therapies.
Transactive response DNA-binding protein (TDP-43) plays a key pathological role in several neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the well-established role of TDP-43 in neurodegenerative disorders, it remains a complex area of study as it is unclear whether nuclear loss-of-function, cytoplasmic gain-of-function, or both drive pathogenesis. TDP-43 overexpression models are advantageous tools when developing drug candidates targeted at TDP-43, however, existing models often lack comprehensive RNA-seq data benchmarked against patient datasets. Given the value of TDP-43 overexpression as a model of ALS-related pathology, we have developed a stable, inducible system in a HEK293-derived cell line, offering a practical and scalable platform to investigate TDP-43 dysregulation. Utilizing this system, we found that TDP-43 overexpression reflected key features associated with ALS pathology, causing cytotoxicity, nucleocytoplasmic mislocalization, and extensive transcriptomic changes. Furthermore, comparative RNA-seq analysis between this model and ALS patient-derived data revealed substantial overlaps, where 64
Alzheimer’s disease (AD) is characterized by cerebral glucose hypome-tabolism, an early hallmark through neuroimaging and neuropathological investigations. Previous researches have established the phenomenon of reduced glucose uptake. Building upon this established knowledge, the field is now increasingly focused on elucidating the underlying molecular mecha-nisms that govern these metabolic changes. In this review, we synthesize current evidence regarding the dysregulation of major glycolytic and pyruvate-metabolizing enzymes, including hexokinase (HK), phosphofructokinase-1 (PFK1), pyruvate kinase (PK), lactate dehydrogenase (LDH), and the pyruvate dehydrogenase complex (PDHc), in both neurons and glial cells. As well as compromising cerebral energy homeostasis, these enzymatic disruptions engage in bidirectional feedback mechanisms with neuroinflammatory pathways and amyloid-β/Tau pathology. By consolidating recent mechanism research, this review offers a potential framework for understanding how metabolic enzyme dysregulation contributes to AD pathogenesis at a molecular level. Emerging therapeutic strategies targeting these metabolic enzymes are also discussed, along with an evaluation of both their preclinical promise and the translational challenges that remain.
