Current Neuropharmacology - Volume 23, Issue 9, 2025

In vitro data from primates provide conflicting evidence about the suitability of the cerebellum as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET).

We first measured mGluR5 density in postmortem human cerebellum using [³H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next, in vivo experiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [¹¹C]ABP688 binding potential (BPND) values obtained with reference tissue methods and the two-tissue compartment model vs. metabolite-corrected arterial input function.

The postmortem data showed that, relative to the hippocampus, the cerebellum had 35% less mGluR5 immunoreactivity and 94% fewer [³H]ABP688 binding sites. In vivo brain regional [¹¹C]ABP688 BPND values using the cerebellum as a reference region were highly correlated with BPND values and distribution volumes derived by arterial input methods (R² > 0.9).

The scarce availability of cerebellar allosteric binding sites at autoradiography, compared to immunohistochemistry results, might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these data support the proposition that [¹¹C]ABP688 BPND using the cerebellum as a reference region provides accurate quantification of mGluR5 allosteric binding in vivo. Studies relying on this method could, therefore, be used in clinical populations, providing that stronger initial assumptions are met.

The investigation aimed to study the outcome of rosiridin in Parkinson's disease (PD) induced by rotenone (ROT) in rodents.

Rodents were randomized into IV groups and were induced with ROT followed by treatment with rosiridin. Group I-IV received saline as a vehicle, II-ROT (0.5 mg/kg S.C) for 28 consecutive days, III and IV- rosiridin 10 and 20 mg/kg orally with ROT. On completion of the experimental duration, behavioral investigations were carried out. Biochemical variables such as acetylcholinesterase (AChE), oxidative stress and antioxidants markers (Malondialdehyde-MDA, glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), anti-inflammatory (Interleukin-1 beta-IL-1β, IL-6, and tumor necrosis factor alpha-TNF-α), alteration in neurotransmitters (Serotonin-5-HT), norepinephrine, and dopamine-DA, along with metabolites such as 5-hydroxy indole acetic acid (5-HIAA), mitochondrial complex I, II, IV, and caspase-3 activity were evaluated at the end of the experiment. Furthermore, molecular docking and dynamics were performed for target ligands.

Rosiridin significantly restored the level of AChE, oxidative stress and antioxidants markers (MDA, GSH, SOD, and CAT), anti-inflammatory (IL-1β, IL-6, and TNF-α), alteration in neurotransmitters, mitochondrial complex I, II, IV, and caspase-3 activity. Rosiridin has a favorable negative binding affinity to AChE (-8.99 kcal/mol). The results of the molecular dynamics simulations indicate that proteins undergo a substantial change in conformational dynamics when binding to rosiridin.

In this study, rosiridin may exhibit neuroprotective properties against the Parkinson's model for treating PD.

The gasotransmitter hydrogen sulfide (H2S) modulates various brain functions, including neuron excitability, synaptic plasticity, and Ca²⁺ dynamics. Furthermore, H2S may stimulate nitric oxide (NO) release from cerebrovascular endothelial cells, thereby regulating NO-dependent endothelial functions, such as angiogenesis, vasorelaxation, and cerebral blood flow (CBF). However, the signaling pathway by which H2S induces NO release from cerebrovascular endothelial cells is still unclear.

Herein, we exploited single-cell imaging of intracellular Ca²⁺, H2S, and NO levels to assess how H2S induces Ca²⁺-dependent NO release from the human cerebrovascular endothelial cell line, hCMEC/D3.

Administration of the H2S donor, sodium hydrosulfide (NaHS), induced a dose-dependent increase in (Ca²⁺)i only in the presence of extracellular Ca²⁺. NaHS-induced extracellular Ca²⁺ entry was mediated by the Ca²⁺-permeable TRPA1 channel, as shown by pharmacological and genetic manipulation of the TRPA1 protein. Furthermore, NaHS-dependent TRPA1 activation led to NO release that was abolished by buffering the concomitant increase in (Ca²⁺)i and inhibiting eNOS. Furthermore, the endothelial agonist, adenosine trisphosphate (ATP), caused a long-lasting elevation in (Ca²⁺)i that was driven by cystathionine γ-lyase (CSE)-dependent H2S production and by TRPA1 activation. Consistent with this, ATP-induced NO release was strongly reduced either by blocking CSE or by inhibiting TRPA1.

These findings demonstrate for the time that H2S stimulates TRPA1 to induce NO production in human brain microvascular endothelial cells. Additionally, they show that this signaling pathway can be recruited by an endothelial agonist to modulate NO-dependent events at the human neurovascular unit.