Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons, resulting in tremor, rigidity, bradykinesia and poor motor coordination. The present study was aimed to evaluate anti-Parkinsonian activity and neuroprotective potential of cardamonin in reserpine and haloperidol induced experimental models of Parkinsonism in mice. Cardamonin is a naturally occurring chalcone that has been reported to possess antioxidant and anti-inflammatory activities and may modulate biological processes associated with oxidative stress and neuroinflammation. Motor and cognitive functions were assessed using behavioral tests including open-field, pole-climbing, catalepsy and novel object recognition tests. Biochemical estimations of lipid peroxidation and endogenous antioxidants status were performed. Further, the tissue levels of dopamine were estimated. Brain tissues were subjected to routine histopathological investigation. Results showed that cardamonin significantly improved motor activity, decreased oxidative stress, enhanced the status of endogenous antioxidants and increased tissue levels of dopamine. Histopathological examination showed attenuation of general histological changes in treated animals. To summarize, the results support the anti-Parkinsonian activity and neuroprotective potential of cardamonin under the experimental conditions. However, direct preservation of dopaminergic neurons was not demonstrated because dopaminergic neuron-specific markers were not evaluated.

Sarcococca saligna (S. saligna), a medicinal plant, has traditionally been used due to its beneficial effects on the nervous system. This study evaluated the anticonvulsant efficacy of S. saligna methanolic extract (SSME) against pentylenetetrazol induced seizures (60 mg/kg) in Wistar rats. Sodium valproate (300 mg/kg, administered orally) served as the reference drug. Rats received SSME at doses of 250, 500, and 1000 mg/kg for seven days. The anticonvulsant potential of SSME was evaluated using neurobehavioral tests and quantifying neurotransmitters and oxidative stress biomarkers. Biochemical and neurochemical tests showed that extract treated rats without seizures showed significant (p < 0.001) restoration of the levels of dopamine (DA), noradrenaline (NA), serotonin, and antioxidant enzymes (SOD, CAT), along with lower levels of malondialdehyde (MDA). Treatment with SSME reinstated these parameters to near normal levels. Furthermore, the extract restored the balance between inhibitory and excitatory neurotransmitters by increasing GABA and maintaining normal glutamate levels in brain homogenates. Histopathological analyses revealed substantial recovery from neuronal degeneration and vacuolization following extract tratment in epileptic rats. The results show that SSME has significant anticonvulsant properties, making it a possible treatment for epilepsy. The findings of current study showed that SSME significantly improved motor function, restored neurotransmitter balance, and maintained antioxidant defenses without producing apparent treatment-related adverse effects under the experimental conditions. These findings suggest that SSME has promise as a potential therapeutic candidate for epilepsy and merits further preclinical and clinical investigation.

Progressive supranuclear palsy is a late-onset neurodegenerative disorder characterized by tau aggregation and prominent dopaminergic dysfunction, yet the upstream molecular processes linking transcriptional abnormalities to dopaminergic failure remain poorly understood. To explore these mechanisms, we performed an integrated multi-omics analysis using a mouse model with overexpression of human filamin-A, a cytoskeletal protein genetically implicated in progressive supranuclear palsy. Analyses were conducted in young adult mice (5-7 months) and aged mice (14-16 months) of both sexes, with transcriptomic, epigenomic, biochemical, metabolomic and behavioural profiling performed across multiple brain regions. In parallel, post-mortem human brain tissue from 11 individuals with progressive supranuclear palsy and five neurologically normal controls was analysed for biochemical validation using samples from the frontal cortex and striatum. Transcriptomic profiling identified immediate early gene-centred transcriptional dysregulation as a prominent and early molecular alteration. This change, accompanied by chromatin accessibility alterations, was associated with the activation of activator protein 1-dependent gene programmes and region-specific changes in dopaminergic protein markers across the cortex, striatum and midbrain. Multi-layered analyses revealed cortical monoamine depletion together with early striatal dopaminergic sensitization, indicating a close association between immediate early gene dysregulation and dopaminergic circuit imbalance. With ageing, the coupling was lost, coinciding with dopaminergic exhaustion and deficits in locomotor, cognitive and social behaviours. In human analyses, post-mortem brain samples from individuals with progressive supranuclear palsy showed reduced dopamine D2 receptor expression compared with neurologically normal controls, together with region-dependent alterations in c-Fos expression and enrichment of activator protein 1-related motifs in regions with reduced chromatin accessibility. Together, these findings suggest that filamin-A-dependent cytoskeletal stress acts as an upstream molecular context in which immediate early gene-centred transcriptional dysregulation emerges and becomes linked to dopaminergic vulnerability in progressive supranuclear palsy.

Copy number variants at the 22q11.2 chromosomal locus, hemizygous 22q11.2 deletions or duplications, are associated with a broad spectrum of neuropsychiatric and other medical conditions. Individuals with a 22q11.2 deletion are at increased risk for developing early-onset Parkinson's disease. The catechol-O-methyltransferase gene at 22q11.2 is involved in dopamine metabolism. While previous studies have examined several aspects of dopamine function in individuals with 22q11.2 copy number variants, striatal dopamine transporter availability, a regulator of synaptic dopamine, has not yet been systematically investigated. Therefore, dopamine transporter availability was quantified in nine adults with a 22q11.2 deletion, nine with a 22q11.2 duplication and eight controls using a brain-dedicated single-photon emission computed tomography (SPECT) system. Specific striatal binding ratios were calculated with the occipital lobe as the reference region. Permutation analysis of covariance controlling for age and sex showed significantly higher striatal dopamine transporter availability in adults with 22q11.2 deletions compared with those with duplications (P = 0.026, η [2] p = 0.30). No significant differences were observed between adults with 22q11.2 copy number variants and controls. These findings suggest distinct nigrostriatal dopaminergic profiles associated with 22q11.2 copy number variant status, which may play a role in shaping frequently occurring neurological and psychiatric phenotypes in these individuals.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder managed primarily through pharmacological dopamine replacement therapies-including levodopa (L-DOPA), dopamine receptor agonists, MAO-B inhibitors, COMT inhibitors, and novel non-dopaminergic agents like adenosine A2A receptor antagonists. However, long-term pharmacotherapy faces major challenges such as motor fluctuations, levodopa-induced dyskinesias, erratic gastrointestinal absorption, and inter-individual response variability. This review systematically synthesizes how dietary habits, macronutrient compositions, dietary patterns (e.g., Western, Eastern, Japanese, Vegetarian, Mediterranean/MIND, Ketogenic), and eating behaviors (such as restrictive eating, compulsive binge eating, and irregular meal timing) serve as critical extrinsic modulators of drug disposition and clinical performance. Multi-dimensional biological mechanisms underpin these interactions: competitive inhibition at LAT1 transporters by dietary large neutral amino acids (LNAAs), food-induced alterations in gastric emptying and hepatic/intestinal enzyme activity (e.g., CYP3A4, CYP1A2, UGT), neuroinflammatory and oxidative stress modulation via nutrient choices, and microbiota-gut-brain axis (MGBA) dynamics involving gut barrier integrity, microbial short-chain fatty acid (SCFA) production, and local bacterial enzymatic degradation of L-DOPA. In real world clinical practice, the absence of precision nutrition frameworks, protein-redistribution diets, targeted chronotherapeutic meal scheduling, and multidisciplinary nutritional support substantially hinders the effective translation of basic pharmacokinetic insights. Consequently, patients frequently encounter formidable clinical challenges, including destabilized pharmacokinetics, recurrent motor complications, and the inability to effectively delay disease progression.

Tyrosine hydroxylase (TH) deficiency is a rare metabolic disorder caused by biallelic pathogenic variants in the TH gene (TH). More than 95% of TH variants can be detected by usual sequence analyses and gene-targeted deletion/duplication analyses are necessary to identify gross abnormalities (e.g., exon deletions). The enzyme TH, a tetrahydrobiopterin (BH4)-dependent monooxygenase, catalyzes the rate-limiting step in catecholamine biosynthesis. Thus, symptoms result from dopamine deficiency and subsequent noradrenaline/adrenaline deficits, and most patients demonstrate positive response to levodopa. The phenotypic spectrum of this treatable disorder is extremely broad. Although the underlying mechanisms of phenotypic heterogeneity are still unknown, recent human and experimental data have indicated that 1) there is no dopaminergic neuronal degeneration in TH deficiency, 2) mildly affected patients may develop dopa-responsive dystonia through dysfunctional D1 dopamine receptors due to congenital dopamine deficiency and insufficient postnatal dopamine increases in the striatum, and 3) severely affected patients may demonstrate remarkable motor development delay in infancy and hypersensitivity to levodopa therapy (leading to levodopa-induced dyskinesias) caused by profound brain dopamine deficit and consequent abnormal synaptic and brain maturation. It is known that, in the normal human brain, development of the nigrostriatal dopaminergic system is incomplete at birth and striatal dopamine, TH, and its cofactor BH4 concentrations significantly increase during postnatal development. Therefore, dopamine deficiency should be corrected by appropriate treatment with levodopa (e.g., very low initial doses for severely affected cases to avoid intolerable levodopa-induced dyskinesias) as soon as genetically diagnosed or upon the appearance of characteristic symptoms of TH deficiency.

Dopamine is a critical neurotransmitter involved in the regulation of motor control, cognition, reward processing, motivation, and neuroendocrine functions. Increasing evidence indicates that disturbances in dopaminergic neurotransmission contribute significantly to the pathogenesis of major neurodegenerative disorders, particularly Parkinson's Disease (PD) and Alzheimer's Disease (AD). The dopaminergic system comprises specialized neuronal populations, dopamine receptors, and transporter proteins that collectively maintain synaptic dopamine homeostasis and neuronal signaling. Degeneration of dopaminergic neurons is a hallmark of PD, whereas emerging studies suggest that impaired dopamine signaling also plays an important role in the cognitive and behavioral deficits associated with AD. This review summarizes current knowledge regarding the involvement of dopaminergic pathways in neurodegeneration, with emphasis on receptor subtypes, dopamine transporter function, and neuronal vulnerability. Furthermore, it discusses established therapeutic interventions, including dopamine receptor agonists and other dopaminergic modulators, highlighting their clinical benefits and limitations. Recent advances in the field, such as biased receptor ligands, gene-based therapies, stem cell-mediated regeneration, and nanoparticle-assisted drug delivery systems, are also evaluated for their potential to enhance therapeutic efficacy and target specificity. In addition, commonly used experimental models for investigating dopaminergic dysfunction and disease progression are reviewed. Despite substantial progress, several translational challenges continue to hinder the development of disease-modifying treatments. A deeper understanding of dopaminergic signaling mechanisms and their interactions with neurodegenerative processes may facilitate the identification of novel therapeutic targets. Future strategies should focus not only on symptomatic management but also on slowing or preventing disease progression through precise modulation of dopaminergic networks.

Over the past five decades, strategies for dopaminergic therapy in Parkinson's disease (PD) have evolved significantly. Historically treatments aimed to reduce parkinsonism symptoms. Later, the focus shifted to preventing motor fluctuations and dyskinesias, leading clinicians to delay levodopa initiation. As knowledge of the mechanisms underlying motor complications, the clinical relevance of non-motor symptoms, and the efficacy and safety profiles of various dopaminergic drug classes increased, clinicians developed a personalized approach to therapy selection. This article reviews the scientific concepts that informed current approaches to dopaminergic therapy in PD. It evaluates clinical studies comparing levodopa and dopamine receptor agonists as initial therapies, the rationale for revising the strategy of delaying levodopa initiation, and current principles for treatment selection at different disease stages. The analysis addresses patient age and age at PD onset, severity of motor and non-motor symptoms, risk factors for motor fluctuations and dyskinesias, cognitive and psychiatric status, and individual susceptibility to adverse effects from dopaminergic therapy. The article also examines the benefits and limitations of different dopaminergic drug classes. The findings suggest that current strategies prioritize personalized and rational use of dopaminergic agents at various stages of PD, tailored to the patient's clinical profile.

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder. Early diagnosis remains challenging because of clinical heterogeneity and symptom overlap with Parkinson's disease and other atypical parkinsonian syndromes. This systematic review synthesizes current evidence on molecular biomarkers of MSA in biological fluids, including cerebrospinal fluid and blood plasma, following PRISMA 2020 guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). It evaluates seven groups of potential biomarkers: aggregated α-synuclein, neurofilament light chains, tau protein, myelin basic protein, neurotransmitters (dopamine, norepinephrine, serotonin, β-endorphins), neuroinflammation markers (cytokines, c), homocysteine, and coenzyme Q10. The review critically assesses their pathophysiological relevance, differential diagnostic and prognostic value, and the limitations and inconsistencies that hinder clinical implementation. It also discusses promising strategies for combining biomarkers.

Fibromyalgia (FM) is a chronic pain disorder characterized by widespread musculoskeletal pain accompanied by fatigue, mood disturbances, and sleep abnormalities. Baricitinib, a selective Janus kinase (JAK) 1/2 inhibitor, has potent anti-inflammatory and immunomodulatory effects and is approved for various resistant inflammatory conditions. The present study aimed to investigate the therapeutic potential of baricitinib against fibromyalgia-like manifestations induced by reserpine in rats. Reserpine (1 mg/kg/day, subcutaneous) was administered for three consecutive days to induce FM-like pathology, followed by oral treatment with baricitinib at low and high doses for 14 consecutive days. Reserpine administration resulted in marked neuroinflammatory changes, evidenced by elevated levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α, along with increased phosphorylation of JAK2, STAT3, PI3K, AKT, and mTOR signaling proteins. Baricitinib treatment significantly ameliorated these molecular alterations and attenuated histopathological damage in the spinal cord. Furthermore, baricitinib partially restored dopamine D2 receptor levels and modulated M1/M2-associated microglial markers, as indicated by reduced CD86 expression and enhanced CD163 immunoreactivity. Additionally, behavioral assessments demonstrated significant improvements in pain sensitivity, locomotor activity, and depressive-like symptoms. These findings highlight the neuroprotective and anti-inflammatory effects of baricitinib in a reserpine-induced fibromyalgia model and support its potential role in targeting neuroimmune mechanisms underlying fibromyalgia.

Breast cancer, including subtypes with limited treatment options, remains a formidable global health challenge. While conventional therapies often suffer from severe off-target toxicity and the rapid development of drug resistance, emerging phototherapies are limited by poor tissue penetration and monotherapy inefficiency. To overcome these clinical hurdles, there is a critical need for multifunctional, multimodal therapeutic platforms. Here, we present mesoporous polydopamine-curcumin nanoparticles (MPDA-Cur) as a multimodal nanoplatform featuring pH-responsive chemotherapy alongside NIR-triggered synergistic photothermal/photodynamic therapy (PTT/PDT) and enhanced ROS generation. MPDA-Cur was synthesized via dopamine polymerization and curcumin loading, yielding spherical nanoparticles (119.21 ± 13.5 nm) with pH-dependent drug release (54.1% at pH 5.5 vs. 40.9% at pH 7.4) and enhanced reducing/phenolic redox activity. Under 808 nm NIR irradiation, MPDA-Cur generated localized hyperthermia (ΔT ≈ 30.8 °C) and increased reactive oxygen species (ROS) production, which, together with curcumin-mediated chemotherapy, resulted in approximately 70% cell death in MCF-7 cells, with Annexin V/PI staining indicating apoptosis as a major mechanism of cell death. Quantitative H2O2 measurement further showed that MPDA-Cur plus NIR irradiation significantly increased intracellular H2O2 levels relative to non-irradiated controls. The nanoplatform exhibited greater cytotoxicity toward MCF-7 cells than toward L-929 fibroblasts under the tested in vitro conditions, while L-929 viability remained >80%, and also demonstrated hemocompatibility. By integrating pH-responsive curcumin release with NIR-triggered photothermal and ROS-associated photodynamic effects, MPDA-Cur addresses several limitations of conventional monotherapies in vitro. This work establishes MPDA-Cur as a promising multifunctional platform for further preclinical investigation in multimodal breast cancer therapy.

Psychostimulant use disorders, particularly cocaine use disorder, is marked by compulsive drug seeking and high relapse rates. Cocaine blocks the dopamine transporter (DAT), preventing dopamine (DA) reuptake, leading to elevated DA signaling-a key driver of its addictive properties. Although behavioral interventions such as contingency management have demonstrated efficacy in treating stimulant use disorders, their long-term effectiveness and accessibility remain limited, and no US Food and Drug Administration-approved pharmacotherapy for psychostimulant use disorder currently exists, highlighting the need for novel treatment options. We investigated the therapeutic potential of KM822, a novel allosteric DAT modulator that binds to a distinct domain different from the cocaine/DA binding site. When infused into the nucleus accumbens, KM822 significantly attenuated cocaine-induced hyperlocomotion of an intracranial dose of 25 μg cocaine, with no significant effect observed at higher cocaine doses tested. To assess the impact of KM822 on cocaine's rewarding properties, we used the conditioned place preference (CPP) test. KM822 pretreatment during conditioning successfully blocked the development of cocaine-induced CPP. To model relapse, we evaluated cocaine-primed reinstatement in the CPP assay and found that KM822 pretreatment before cocaine priming effectively blocked reinstatement behavior. Importantly, KM822 alone did not produce preference in the CPP test, suggesting that KM822 has low abuse potential. At the protein level, KM822 alone did not significantly alter c-Fos expression, a marker of neuronal activation, but attenuated cocaine-induced c-Fos expression. Together, these findings demonstrate that KM822 can inhibit cocaine-related behaviors and neural responses and serve as a proof of concept for the therapeutic potential of allosterically targeting DAT. SIGNIFICANCE STATEMENT: This project provides proof of concept that targeting the dopamine transporter allosteric site with modulators such as KM822 offers a promising strategy for developing pharmacotherapies for psychostimulant use disorder, especially cocaine use disorder.