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Introduction: The rhizomes of Alpinia galanga (L.) Willd (Zingiberaceae) commonly known as greater galangal, a ginger substitute for food and was traditionally used as nervine tonic and stimulant. The present study was designed to screen the neuroprotective role of hydroalcoholic extract of rhizome of Alpinia galanga (HAAG) in transient forebrain ischemia induced neuronal damage and oxidative injury in the rat brain. Materials and Method: The transient forebrain ischemia was induced by bilateral common carotid artery occlusion in anesthetized rats for 60 min, followed by reperfusion injury. The transient forebrain ischemia induced neuronal damage and oxidative stress was assessed by estimating the percentage survival neurons in the Cornu ammonis CA1 and CA3 regions of hippocampus, MDA levels and antioxidant enzymes activities in the brain homogenate. Open field, actophotometer and grip strength tests were used for behavioral assessment. Recovery in spontaneous motor activity in actophotometer test and number of squares crossed and rearing behavior in the open field test are indicators of cognitive enhancement after treatment with Alpinia galanga. Results and Discussion: Treatment with Alpinia galanga attenuated the delayed neuronal death in the CA1 and CA3 regions of hippocampus. Reduced post-ischemic brain tissue MDA levels at both the drug doses and increased antioxidant enzyme such as glutathione peroxidase at a higher dose was also noted, which indicates Alpinia galanga is neuroprotective against ischemic hippocampal injury. The present study demonstrated that treatment with HAAG attenuated forebrain ischemic reperfusion induced neuronal injury and oxidative stress in hippocampus. Conclusion: Treatment with Alpinia galanga may have the potential to be used as a protective agent in forebrain ischemic injury. [ABSTRACT FROM AUTHOR]

GBA mutations are major risk factors for Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), two common α-synucleinopathies associated with cognitive impairment. Here, we investigated the role of GBA mutations in cognitive decline by utilizing Gba L444P mutant mice, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but no PD-like motor deficits up to 12 months old. Conversely, SNCA tg mice displayed age-related motor deficits but no cognitive abnormalities. Gba-SNCA mice exhibited exacerbated motor deficits and cognitive decline. Immunohistological analysis revealed cortical phospho-α-synuclein pathology in SNCA tg mice, which was exacerbated in Gba-SNCA mice, especially in layer 5 cortical neurons. Significantly, Gba mutant mice did not show α-synuclein pathology. Single-nucleus RNA sequencing of cortices instead uncovered selective synaptic vesicle cycle defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via robust downregulation in gene networks regulating synapse vesicle cycle and synapse assembly. Meanwhile SNCA tg mice displayed broader synaptic changes. Immunohistochemical and electron microscopic analyses validated these findings. Together, our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, likely involving dysfunction in synaptic vesicle endocytosis. Additionally, Gba-SNCA mice are a valuable model for studying cognitive and motor deficits in PD and DLB., Competing Interests: Conflicts of interest: Authors have no conflicts of interest to declare.

Auxilin (DNAJC6/PARK19), an endocytic co-chaperone, is essential for maintaining homeostasis in the readily releasable pool (RRP) by aiding clathrin-mediated uncoating of synaptic vesicles. Its loss-of-function mutations, observed in familial Parkinson's disease (PD), lead to basal ganglia motor deficits and cortical dysfunction. We discovered that auxilin-knockout (Aux-KO) mice exhibited impaired pre-synaptic plasticity in layer 4 to layer 2/3 pyramidal cell synapses in the primary visual cortex (V1), including reduced short-term facilitation and depression. Computational modeling revealed increased RRP refilling during short repetitive stimulation, which diminished during prolonged stimulation. Silicon probe recordings in V1 of Aux-KO mice demonstrated disrupted visual cortical circuit responses, including reduced orientation selectivity, compromised visual mismatch negativity, and shorter visual familiarity-evoked theta oscillations. Pupillometry analysis revealed an impaired optokinetic response. Auxilin-dependent pre-synaptic endocytosis dysfunction was associated with deficits in pre-synaptic plasticity, visual cortical functions, and eye movement prodromally or at the early stage of motor symptoms., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT 2 receptor agonist, exhibits modest selectivity over 5-HT 1 receptors, has no relevant activity at 5-HT 4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (G q , G 11 , and β-arrestin2) coupled to 5-HT 2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between G q/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT 2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT 2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT 2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT 2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Asian-Indians are less vulnerable to Parkinson's disease (PD) than the Caucasians. Their admixed populace has even lesser risk. Studying this phenomenon using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their resistant crossbred mice revealed differences in the nigrostriatal cyto-molecular features. Here, we investigated the electrophysiological and behavioural correlates for differential MPTP-susceptibility and their outcome upon admixing. We recorded local field potentials (LFPs) from dorsal striatum and assessed motor co-ordination using rotarod and grip strength measures. Nigral calbindin-D28K expression, a regulator of striatal activity through nigrostriatal projections was evaluated using immunohistochemistry. The crossbreds had significantly higher baseline striatal LFPs. MPTP significantly increased the neuronal activity in delta (0.5-4 Hz) and low beta (12-16 Hz) ranges in C57BL/6J; significant increase across frequency bands till high beta (0.5-30 Hz) in CD-1, and caused no alterations in crossbreds. MPTP further depleted the already low nigral calbindin-D28K expression in C57BL/6J. While in crossbreds, it was further up-regulated. MPTP affected the rotarod and grip strength performance of the C57BL/6J, while the injected CD-1 and crossbreds performed well. The increased striatal β-oscillations are comparable to that in PD patients. Higher power in CD-1 may be compensatory in nature, which were also reported in pre-symptomatic monkeys. Concurrent up-regulation of nigral calbindin-D28K may assist maintenance of striatal activity by buffering calcium overload in nigra. Thus, preserved motor behaviour in PD reminiscent conditions in CD-1 and crossbreds complement compensated/unaffected striatal LFPs. Similar electrophysiological correlates and cytomorphological features are envisaged in human phenomenon of differential PD prevalence, which are modulated upon admixing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ischemic brain injury is one of the leading causes of death and disability, where lack of disease modifying treatment strategies make us rely on symptomatic relief. Treatment principles from traditional systems of medicine may fill this gap and its validation in modern medicine perspective is important to bring them to mainstream. Here, we evaluated the neuroprotective efficacy of Ayurvedic medicinal herb Pluchea lanceolata in treating ischemic hippocampal injury. Focal hippocampal ischemia was modeled in Wistar rats through stereotaxic intrahippocampal injection of endothelin-1 (ET-1). Post-surgery, hydroalcoholic extract of the rhizome of Pluchea lanceolata (HAPL) was administered orally, once in a day for 14 consecutive days to ischemic rats. There were two treatment groups based on the HAPL dosage; HAPL200 (200 mg/kg body weight) and HAPL400 (400 mg/kg body weight). Comparisons were made with the ET-1 ischemic rats which received only the vehicle, and the normal surgical control. Ischemic hippocampal injury led to severe cognitive deficits as evaluated by Morris water maze and open field test, along with locomotory dysfunction noted in actophotometer test. HAPL treatment significantly attenuated these behavioural deficits in a dose dependent manner. Loss of pyramidal cells and degenerative phenotype of shrunken hyperdensed soma with pyknotic nuclei in CA1 and CA3 hippocampal neurons in ischemia were reversed after HAPL treatment. We provide first evidence for loss of dendritic architecture in ET-1 induced focal ischemic hippocampal injury using Golgi impregnation, where HAPL could salvage the dendritic branching and intersections. Intriguingly, it enhanced the dentritic arborization beyond what is noted in normal rats. Ability of HAPL to reverse oxidative stress, especially through maintaining glutathione peroxidase levels and lipid peroxidation in ischemic condition evidences that it may exert neuroprotection through its antioxidant properties. Thus, Pluchea lanceolata and its constituents provide potential alternative/adjuvant treatment strategy for ischemic hippocampal stroke., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) affects the A9 dopaminergic (DA) neurons of substantia nigra pars compacta (SNpc) whereas other DA neuronal subtypes are spared. The role of calbindin in this differential vulnerability has been long elicited, and is seen in the MPTP induced mice models of PD. A peculiar feature of mice models is the strain specific differences in the susceptibility to MPTP. Here, calbindin-D28K expression in DA neurons of SNpc of MPTP susceptible C57BL/6 mice and MPTP resistant CD-1 mice was studied as a susceptibility marker of degeneration. Unbiased stereological estimation of immunoperoxidase stained midbrain sections revealed significantly higher number of calbindin immunoreactive cells in SNpc of CD-1 mice compared to that of C57BL/6 strain. Western blotting showed minimal differences in the levels. Calbindin-tyrosine hydroxylase immunofluorescence co-labeling was performed to map the calbindin immunoreactive DA neurons in SNpc and ventral tegmental area (VTA) and to quantify the calbindin expression at cellular level. While the levels were comparable in VTA of both mice strains, the SNpc of CD-1 mice showed significantly higher calbindin expression. Within the SNpc, the medial and dorsal subdivisions showed higher calbindin expression in CD-1. The expression in the ventrolateral SNpc of both strains remained comparable. Our observations clearly point at overall higher levels and sizeable percentage of cells expressing more calbindin in SNpc of CD-1 mice, which might confer neuroprotection against MPTP, while its lower expression makes C57BL/6 mice more susceptible. Similar mechanism may be attributed to the phenomenon of differential prevalence of PD in different ethnic populations., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Age being a risk factor for Parkinson's disease, assessment of age-related changes in the human substantia nigra may elucidate its pathogenesis. Increase in Marinesco bodies, α-synuclein, free radicals and so forth in the aging nigral neurons are clear indicators of neurodegeneration. Here, we report the glial responses in aging human nigra. The glial numbers were determined on Nissl-stained sections. The expression of glial fibrillary acidic protein, S100β, 2', 3'-cyclic nucleotide 3' phosphodiesterase, and Iba1 was assessed on cryosections of autopsied midbrains by immunohistochemistry and densitometry. The glial counts showed a biphasic increase, of which, the first prominent phase from fetal age to birth could be physiological gliogenesis whereas the second one after middle age may reflect mild age-related gliosis. Astrocytic morphology was altered, but glial fibrillary acidic protein expression increased only mildly. Presence of type-4 microglia suggests possibility of neuroinflammation. Mild reduction in 2', 3'-cyclic nucleotide 3' phosphodiesterase-labeled area denotes subtle demyelination. Stable age-related S100β expression indicates absence of calcium overload. Against the expected prominent gliosis, subtle age-related morphological alterations in human nigral glia attribute them a participatory role in aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)