Parkinson’s disease (PD) is the fastest-growing neurological disease worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Epidemiological, post-mortem, and mechanistic studies suggest that persistent organic pollutants, including the organochlorine pesticide dieldrin, increase PD risk. In mice, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and synucleinopathy. Specifically, in the α-synuclein (α-syn) pre-formed fibril (PFF) model, exposure leads to increased deficits in striatal dopamine (DA) turnover and motor deficits on the challenging beam. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF 2-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days by feeding, starting at 8 weeks of age and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of α-syn PFFs at 12 weeks of age, and vesicular ³H-DA uptake assays and fast-scan cyclic voltammetry were performed 4 months post-PFF injection. Dieldrin-induced an increase in DA release in striatal slices in PFF-injected animals, but no change in VMAT2 activity. These results suggest that developmental dieldrin exposure increases a compensatory response to synucleinopathy-triggered striatal DA loss. These findings are consistent with silent neurotoxicity, where developmental exposure to dieldrin primes the nigrostriatal striatal system to have an exacerbated response to synucleinopathy in the absence of observable changes in typical markers of nigrostriatal dysfunction and degeneration.

Craniopharyngiomas are rare, histologically benign but locally aggressive intracranial tumors that are associated with substantial visual, endocrine, and hypothalamic morbidity. Advances in molecular characterization have enabled the use of systemic molecularly targeted therapies, particularly in the recurrent or refractory setting, with the goal of limiting further surgical or radiation-related injury to the hypothalamic–pituitary axis. Papillary craniopharyngioma (PCP), defined by near-universal BRAF V600E mutations, exhibits profound and rapid responses to combined BRAF and MEK inhibition, with objective response rates exceeding 90% in prospective studies. These responses can facilitate less extensive surgery, enable de-escalation of radiotherapy, or allow deferral of local treatment. In contrast, adamantinomatous craniopharyngioma (ACP), characterized by CTNNB1 mutations and a cystic phenotype with a prominent inflammatory microenvironment, lacks a single actionable oncogenic driver. Early clinical experience suggests that Interleukin-6/Interleukin-6 receptor (IL-6/IL-6R) blockade, alone or in combination with bevacizumab, may stabilize or reduce cystic components in selected patients, although evidence remains limited to small case series. Other systemic approaches for ACP, including MAPK pathway inhibition and immune-directed strategies, are still under investigation. Across subtypes, adverse events have generally been class-expected and manageable, but data on long-term endocrine, hypothalamic, and neurocognitive outcomes are sparse. This review synthesizes current evidence for neoadjuvant, adjuvant, and palliative craniopharyngioma systemic targeted therapies and highlights the ongoing clinical considerations of this therapy.

Parkinson’s disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the α-synuclein (α-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of α-syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular ³ H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover. Graphical