Aug 2026· Journal of Parkinson's Disease· 0 citations· 88 references
Medicine
TL;DR
By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.
Abstract
Background Neuropsychiatric symptoms such as anxiety and depression substantially impair quality of life in Parkinson's disease (PD), yet the underlying neural circuits remain poorly defined. The MitoPark (MP) mouse, a dopaminergic mitochondrial dysfunction model, recapitulates both motor and non-motor features of PD. Objective To determine whether the sustained-release GLP-1 receptor agonist PT320 (exenatide) alleviates anxiety- and depression-like behaviors in MP mice and to identify the involved neural substrates. Methods The temporal progression of anxiety- and depression-like behaviors was characterized in MP mice. PT320 was administered biweekly starting at either 5 weeks (early treatment) or 15 weeks (late treatment), with longitudinal evaluation until 20 weeks. Behavioral outcomes were correlated with molecular, transcriptomic, and neurochemical analyses in the nucleus accumbens (NAc), including Western blotting, bulk RNA sequencing, fast-scan cyclic voltammetry, and tyrosine hydroxylase immunostaining. Results Early PT320 treatment effectively prevented the emergence of anxiety- and depression-like phenotypes in MP mice. Behavioral improvement was associated with restoration of BDNF signaling and activation of the Akt–CREB pathway in the NAc. Transcriptomic analysis revealed increased expression of Akt3, CREB, BDNF, and TrkB, along with modulation of genes related to mitochondrial homeostasis. Late PT320 treatment partially ameliorated neuropsychiatric deficits, coinciding with enhanced phasic dopamine release and recovery of tyrosine hydroxylase expression in the NAc. Conclusions These findings identify the NAc as a critical regulator of affective disturbances in this PD model. By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression.
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
Parkinson's disease (PD) is characterized by motor deficits and debilitating non-motor symptoms (NMS), including depression, anxiety, and cognitive impairment. While current therapies alleviate motor dysfunction, NMS management remains a critical unmet need. Pramipexole (PPX), a non-ergoline dopamine agonist with high selectivity for D2/D3 receptors (particularly D3), demonstrates potential for multi-target modulation beyond motor improvement. To systematically evaluate the efficacy of PPX against NMS and elucidate its novel mechanism involving autophagy regulation, a dual neurotoxin-induced PD mouse model (MPTP and DSP-4; MPTP:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DSP-4: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) recapitulating both motor and NMS was employed. PPX significantly improved NMS, reducing anxiety/depressive -like behavior and cognitive decline, alongside restoring motor function. Moreover, PPX administration promoted survival of dopaminergic and noradrenergic neurons and preserved synaptic integrity in a double lesion model of PD. In our molecular detection, PPX treatment was accompanied by enhanced key components of autophagy (Beclin-1/P62) and rectified deficient mitophagy (BNIP3L/PINK1/Parkin). This study identifies PPX as a dual-action therapeutic that concurrently alleviates motor/NMS in PD model mice, and this therapeutic effect may be associated with altered expression of autophagy-related proteins.
Shimin Pang, Jingyue Liu, Linghui Sheng et al.· Brain Research Bulletin· 0 citations
BACKGROUND
Parkinson's disease (PD) is a prevalent neurodegenerative disorder hallmarked by progressive loss of midbrain dopaminergic (DA) neurons, neurite atrophy, neurotransmitter imbalance, and motor dysfunction. Therapeutic strategies targeting neuronal integrity and neuroinflammation hold translational value beyond conventional symptomatic therapies for PD. Sarsasapogenin, a natural steroidal saponin, exhibits documented neuroprotective properties in multiple neurological diseases. However, its therapeutic potential and underlying mechanisms in PD remain to be elucidated.
METHODS
The neuroprotective efficacy of sarsasapogenin was assessed in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model and 1-methyl-4-phenylpyridinium ion (MPP+)-insulted primary cortical and dopaminergic neuronal cultures. Motor function was evaluated via a variety of behavioral tests. Survival of dopaminergic neurons was quantified using tyrosine hydroxylase (TH) immunostaining. Levels of monoamine neurotransmitters and their metabolites were measured using high-performance liquid chromatography (HPLC), while serum proinflammatory cytokines were determined using enzyme-linked immunosorbent assay (ELISA). Neurite outgrowth and neuronal viability were examined under both preventive and therapeutic treatment regimens in vitro. Potential molecular targets of sarsasapogenin were screened and identified via Drug Affinity Responsive Target Stability (DARTS) coupled with molecular docking.
RESULTS
Twenty-one-day sarsasapogenin intervention mitigated aberrant motor deficits in MPTP-treated mice, rescued TH+ dopaminergic neurons in the substantia nigra, restored homeostasis of dopamine and norepinephrine, normalized the turnover of monoamines, and decreased peripheral levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). In primary neuronal cultures, sarsasapogenin significantly ameliorated MPP+-triggered neurite atrophy and neuronal loss in both cortical and ventral mesencephalic dopaminergic neurons. DARTS screening combined with molecular docking identified serpin family H member 1 (Serpin) H1 as a candidate binding protein of sarsasapogenin, with a favorable binding affinity of -8.6 kcal/mol.
CONCLUSIONS
Sarsasapogenin exerts comprehensive neuroprotective effects in preclinical PD models via synergistic modulation of dopaminergic neuronal survival, neurotransmitter balance, inflammatory inhibition, and neurite outgrowth. These findings highlight sarsasapogenin as a promising multi-target candidate for PD intervention, whereas the precise functional role of Serpin H1 in mediating its neuroprotective actions warrants further in-depth investigation.
Wendi Deng, Jinfeng Hong, Weixia Li et al.· Journal of Integrative Neuro...· 0 citations
AIMS
Major depressive disorder (MDD) represents a major contributor to disability, yet currently prescribed monoamine-based antidepressants are limited by modest therapeutic efficacy and delayed clinical onset. Recent studies have demonstrated that ketamine, an N-methyl-d-aspartate receptor antagonist, rapidly engages mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex (mPFC), critically linked to its fast-acting antidepressant actions. Shikimic acid (SA), a natural compound widely found in various plants, has been reported to exhibit mTORC1-related signaling activity. In this study, we investigated whether SA induces antidepressant-like behavioral responses through mTORC1-related signaling in the mPFC.
MATERIALS AND METHODS
Antidepressant-like effects of SA were assessed in male and female outbred ICR and inbred C57BL/6 J mice using the forced swim test (FST), with locomotor activity evaluated in the open field test. The role of mTORC1 signaling was evaluated by systemic and intra-mPFC administration of the mTORC1 inhibitor rapamycin. The antidepressant-like effects of SA were further examined in ovariectomized (OVX) mice, a model of menopause-associated depression.
KEY FINDINGS
SA significantly reduced immobility in the FST in naïve male but not female ICR mice, and this effect was abolished by systemic and intra-mPFC rapamycin. Comparable effects were observed in naïve male, but not female, C57BL/6 J mice. SA also reversed OVX-induced increase in immobility, and this effect was completely prevented by intra-mPFC rapamycin.
SIGNIFICANCE
These findings suggest that SA exerts antidepressant-like effects via rapamycin-sensitive mTORC1-dependent mechanisms within the mPFC. Our results support SA as a candidate compound targeting mPFC mTORC1-related signaling for novel rapid-acting antidepressants.
Satoshi Deyama, Kana Ito-Shintai, Rinako Sugie et al.· Life Science· 0 citations
Parkinson's disease is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons. Enavogliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor, has recently been demonstrated to exert neuroprotective effects. However, whether enavogliflozin can ameliorate motor behavioral deficits in Parkinson's disease currently remains unclear. To this end, this study aimed to investigate the neuroprotective effects of enavogliflozin on Parkinson's disease and explore its underlying molecular mechanisms. We established a Parkinson's disease model using rotenone-induced C57BL/6 mice (1.5 mg/kg/d, 3 weeks, i.p.) to investigate the neuropharmacological modulation effects of enavogliflozin treatment (0.1 and 1 mg/kg/d, 3 weeks, p.o., 2 h after rotenone injection) on Parkinson's disease from the perspectives of motor behavioral evaluation, pathological changes, oxidative stress, neuroinflammation, and SIRT1/PINK1/Parkin signaling pathways in specific brain regions. The results revealed that enavogliflozin alleviated neuropathological alterations of the substantia nigra, upregulated tyrosine hydroxylase and dopamine transporter expression in nigrostriatal dopaminergic neurons, and improved motor behavioral deficits. Administration of enavogliflozin further significantly reduced the levels of inflammatory cytokines (IL-6 and TNF-α), microglial activation, and oxidative damage in rotenone-induced Parkinson's disease mice. Moreover, we found that enavogliflozin activated PINK1/Parkin-mediated mitophagy by SIRT1 signaling pathway. In conclusion, enavogliflozin ameliorates motor dysfunction in rotenone-induced Parkinson's disease mice by attenuating oxidative stress, inhibiting neuroinflammation, and activating SIRT1/PINK1/Parkin pathway. These findings support a neuroprotective and preventive role for enavogliflozin in Parkinson's disease.
T. Liang, Xiaoyan Pang, Qiaoqiao Liu et al.· Neuropharmacology· 0 citations
Alzheimer's disease (AD) is increasingly associated with early circuit dysfunction preceding cognitive decline, including neuronal hyperactivity and neuropsychiatric symptoms linked to mesolimbic pathways. The nucleus accumbens (NAc), a central regulator of reward and motivational processing, exhibits early alterations in excitation/inhibition balance in patients and experimental models, yet the synaptic mechanisms underlying its vulnerability remain unclear. Using a double transgenic APP/PS1 mice crossed with a Drd1a-tdTomato reporter line, we combined cell-type-specific electrophysiology, immunohistochemistry, ex vivo photometry, and behavioral assays. At a pre-plaque stage, intraneuronal Aβ accumulated in both dopamine D1 receptor-positive (D1R+) and D1R-negative medium spiny neurons (MSNs). Despite comparable Aβ levels, both high-frequency stimulation-induced long-term depression (LTD) and mGluR1/5-dependent LTD were selectively impaired in D1R+ MSNs. This vulnerability was accompanied by an increased contribution of calcium-permeable AMPA receptors (CP-AMPARs). Subsequent CP-AMPAR blockade reduced the residual evoked excitatory postsynaptic current that persisted after mGluR1/5 activation in APP/PS1 D1R+ MSNs. Because paired-pulse ratios remained unchanged, this residual response was consistent with a predominantly postsynaptic mechanism. These synaptic changes were accompanied by reduced evoked dopamine signaling, increased chocolate consumption, and altered baseline context preference, whereas standard pellet consumption, conditioned place preference, anxiety-like behavior, and social behavior were unchanged. These findings define a pre-plaque, cell-type-specific synaptic phenotype in male APP/PS1 mice in which impaired mGluR1/5-dependent plasticity and persistent CP-AMPAR signaling in D1R+ MSNs coincide with selective reward-related alterations.
Nicolás Riffo-Lepe, Juliana González-Sanmiguel, Isaías Meza et al.· Neurobiology of Disease· 0 citations