Perturbation of serine enantiomers homeostasis in the striatum of MPTP-lesioned monkeys and mice reflects the extent of dopaminergic midbrain degeneration.

Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.

AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.

Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Serotonin 5-HT1A receptors and their interactions with adenosine A2A receptors in Parkinson's disease and dyskinesia.

The dopamine neuronal loss that characterizes Parkinson's Disease (PD) is associated to changes in neurotransmitters, such as serotonin and adenosine, which contribute to the symptomatology of PD and to the onset of dyskinetic movements associated to levodopa treatment. The present review describes the role played by serotonin 5-HT1A receptors and the adenosine A2A receptors on dyskinetic movements induced by chronic levodopa in PD. The focus is on preclinical and clinical results showing the interaction between serotonin 5-HT1A receptors and other receptors such as 5-HT1B receptors and adenosine A2A receptors. 5-HT1A/1B receptor agonists and A2A receptor antagonists, administered in combination, contrast dyskinetic movements induced by chronic levodopa without impairing motor behaviour, suggesting that this drug combination might be a useful therapeutic approach for counteracting the PD motor deficits and dyskinesia associated with chronic levodopa treatment. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

Characterization of Nasco grape pomace-loaded nutriosomes and their neuroprotective effects in the MPTP mouse model of Parkinson's disease.

Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT-positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration.

Protective effect of alpha mangostin on rotenone induced toxicity in rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive, late-onset, and degenerative disorder that affects the central nervous system with an unknown etiology. Due to its incredible complexity in disease nature, many of the existing treatment approaches show a vain recovery in Parkinson's patients. Therefore, an in search of disease-modifying therapeutics for an effective recovery is essential. Alpha mangostin is an important polyphenolic xanthone reported for its neuroprotective effect against rotenone-induced α-synuclein aggregation and loss of tyrosine hydroxylase positive (TH+)-neurons in SH-SY5Y cells. Hence, the current study aims to test its protective effect in managing the in-vivo rat model of PD. To justify this aim, adult male Sprague Dawley rats (250 ± 20 g) were subjected to chronic treatment of rotenone (2 mg/kg/day, s.c.) for 21 days. In parallel alpha mangostin treatment (10 mg/kg, i.p) was administered along with rotenone for 21 days. Chronic rotenone treatment for 21 days increased lipid peroxidation, nitrite concentration, and decreased glutathione levels. Further, depletion of TH+-dopaminergic neuron expression in substantia nigra pars compacta (SNc), and the development of motor and behavioral deficits in rotenone treated animals like cognitive impairment, muscle incoordination, and neuromuscular weakness were observed. Moreover, western blot studies ascertained the reduced normal alpha-synuclein levels and increased phosphorylated α-synuclein levels in comparison to the vehicle-treated group. Treatment with alpha mangostin significantly restored the locomotor activity, memory deficits, and improved the levels of antioxidant enzymes. It also significantly reduced the levels of phosphorylated α-synuclein which in turn gave protection against TH+-dopaminergic neuronal loss in SNc, suggesting it's anti-oxidant and anti-aggregatory potential against α-synuclein. In conclusion through our current results, we could suggest that alpha mangostin has a potential neuroprotective effect against rotenone-induced PD and might be used as a neuroprotective agent. Further mechanistic studies on preclinical and clinical levels are required to be conducted with alpha mangostin to avail and foresee it as a potential agent in the treatment and management of PD.

A Cleaning Crew: The Pursuit of Autophagy in Parkinson's Disease.

Parkinson's disease (PD) is the second-most common neurodegenerative disorder, neuropathologically characterized by the aggregation of misfolded α-synuclein (α-syn) protein, which appears to be central to the onset and progression of PD pathology. Evidence from pioneering studies has highly advocated the existence of impaired autophagy pathways in the brains of PD patients. Autophagy is an evolutionarily conserved, homeostatic mechanism for minimizing abnormal protein aggregates and facilitating organelle turnover. Any aberration in constitutive autophagy activity results in the aggregation of misfolded α-syn, which, in turn, may further inhibit their own degradation-leading to a vicious cycle of neuronal death. Despite the plethora of available literature, there are still lacunas existing in our understanding of the exact cellular interplay between autophagy impairment and α-syn accumulation-mediated neurotoxicity. In this context, clearance of aggregated α-syn via up-regulation of the autophagy-lysosomal pathway could provide a pharmacologically viable approach to the treatment of PD. The present Review highlights the basics of autophagy and detrimental cross-talk between α-syn and chaperone-mediated autophagy, and α-syn and macroautophagy. It also depicts the interaction between α-syn and novel targets, LRRK2 and mTOR, followed by the role of autophagy in PD from a therapeutic perspective. More importantly, it further updates the reader's understanding of various newer therapeutic avenues that may accomplish disease modification via promoting clearance of toxic α-syn through activation of autophagy.