Liliana Mendieta

Introduction: Parkinson’s Disease (PD) is a prevalent neurodegenerative disorder characterized by motor and non-motor manifestations that significantly impact quality of life. Increasing evidence suggests that alterations in the gut microbiota and the gut–brain axis may contribute to its pathophysiology. Although probiotics have been widely studied for gastrointestinal symptoms, their potential effects on non-gastrointestinal outcomes remain unclear. Therefore, this study aimed to systematically review the evidence from RCTs assessing the non-gastrointestinal effects of probiotic supplementation in patients with PD. Methods: A systematic search was conducted in PubMed, ScienceDirect, and ClinicalTrials databases. Seven RCTs involving a total of 475 participants with PD met the inclusion criteria. Results: Despite variability in probiotic strains and dosages, supplementation with ≥ 1 × 109 CFU of Lactobacillus spp. and Bifidobacterium spp. for 12 weeks was associated with improvements in depression and anxiety symptoms, as well as reductions in inflammatory markers and insulin resistance in some studies. However, findings were inconsistent across studies, and no significant effects were observed on motor symptoms. Discussion: These findings suggest that probiotics may exert beneficial effects beyond gastrointestinal outcomes, potentially through modulation of the gut–brain axis, systemic inflammation, and metabolic pathways. However, heterogeneity in study designs and strains limits generalizability. Further high-quality, long-term RCTs are needed to confirm efficacy, clarify mechanisms, and establish clinical recommendations. Conclusion: Probiotic supplementation appears to offer promising non-gastrointestinal benefits for individuals with PD, but evidence remains preliminary.

Neuroinflammation is recognized as a central mechanism in Parkinson’s disease (PD) pathogenesis. The C-terminal domain of the heavy-chain of tetanus toxin (Hc-TeTx) has shown neuroprotective effects in toxin-based PD models, but its efficacy in inflammatory-induced PD conditions remain unexplored. To test this possibility, we used the hemiparkinsonism model induced by central injection of lipopolysaccharide (LPS) to evaluate potential antiinflammatory effects of Hc-TeTx in adult male Wistar rats. Seven days post LPS-injection motor coordination and gait maintenance were assessed using elevated beam test. The day after, that is 8 days post LPS-injection, the cylinder test was used to assess forelimb motor asymmetry during spontaneous vertical exploration. Immediately after this test the animals were sacrificed for tissue collection. Dopaminergic degeneration was assessed by immunohistochemical quantification of tyrosine hydroxylase in substantia nigra pars compacta . Astroglial activation, reflective of neuroinflammation was evaluated by glial fibrillary acidic protein in the striatum. LPS administration caused forelimb motor asymmetry, which was significantly attenuated by Hc-TeTx treatment. Hc-TeTx also tended to attenuate LPS-induced dopaminergic neurodegeneration reflected by a reduced TH ipsilateral/contralateral ratio, as well as astroglial activation that was markedly increased after LPS administration. Beam test parameters showed no significant differences among groups. Although further verification and mechanistic studies are needed, current results support potential utility of Hc-TeTx in an inflammatory model of PD.

With the advent of medical technology and the sustenance of a longer lifespan, an increase in the number of age-related neurodegenerative diseases, including Parkinson’s disease (PD), is inevitable. Although current treatments for PD provide remarkable symptomatic relief for a few years, their side effects, combined with the progression in neurodegeneration, pose an urgent challenge for development of more effective treatments for this devastating disease. The challenge is further exacerbated by the unknown etiology in most PD cases. Nonetheless, progress in early identification of the premorbid/prodromal symptoms as well as understanding processes leading to their manifestation may help provide novel preventive and/or intervention strategies. The triad of the best-characterized and inter-related symptoms of prodromal PD include hyposmia (decrease sense of smell), constipation, and major depressive disorder (MDD). Recent revelations indicate a crucial role for the gut microbiota (GM) not only in maintaining the integrity of the gastrointestinal system but also that of the central nervous system via its bidirectional relationship with the brain, commonly referred to as the gut-brain-axis (GBA). Moreover, neuroinflammation, underscored by microglial activation, is believed to play a critical role in neurodegenerative as well as neuropsychiatric disorders including MDD. Here, we delve into the primary roles of GM/GBA and microglia, as well as their interactions, with the aim of providing novel diagnostic and/or treatments in PD. Regarding the treatments, we mention potential use of pre- post- or pro-biotics, and nicotinic or toll-like receptor modulators.

It is well established that the gut-brain axis (GBA) is a bidirectional communication between the gut and the brain. This axis, critical in maintaining overall homeostasis, is regulated at the neuronal, endocrine, and immunological levels, all of which may be influenced by the gut microbiota (GM). Therefore, dysbiosis or disruption in the GM may have serious consequences including neuroinflammation due to overactivation of the immune system. Strategies to reestablish GM integrity via use of probiotics are being pursued as novel therapeutic intervention in a variety of central and peripheral diseases. The mechanisms leading to dysbiosis or efficacy of probiotics, however, are not fully evident. Here, we performed computational analysis on two major probiotics, namely Lactobacillus Lacticaseibacillus rhamnosus GG (formerly named Lactobacillus rhamnosus, L. rhamnosus GG) and Bifidobacterium animalis spp. lactis (B. lactis or B. animalis) to not only shed some light on their mechanism(s) of action but also to identify potential molecular targets for novel probiotics. Using the PubMed web page and BioCyc Database Collection platform we specifically analyzed proteins affected by metabolites of these bacteria. Our results indicate that peroxisome proliferator-activated receptors (PPARs), nuclear receptor proteins that are involved in regulation of inflammation are key mediators of the neuroactive effect of probiotics.

The β-secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer’s disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer’s with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer’s disease, especially those targeting BACE-1.

It is now well recognized that a bidirectional relationship between gut microbiota and the brain, referred to as the gut-brain axis, plays a prominent role in maintaining homeostasis and that a disruption in this axis can result in neuroinflammatory response and neurological disorders such as Parkinson’s disease (PD). The protective action of probiotics such as Bifidobacterium animalis ssp. lactis Bb12 and Lactobacillus rhamnosus GG in various animal models of PD has been reported. Therefore, in this study, we used an inflammatory model of PD to assess the effects of a combination of these two probiotics (Microbiot^®) on motor behavior as well as on the response of microglia, including microglia morphology, to gain a better understanding of their mechanism of action. Microbiot^® (300 µL) was administered orally once daily for 15 days in a lipopolysaccharide-induced PD model using male Wistar rats. Although LPS-induced motor asymmetry in cylinder test was not affected by Microbiot^®, impairment of motor coordination in the narrow-beam test was significantly reduced by this probiotic. Moreover, Microbiot^® treatment reduced microglial activation suggesting an anti-inflammatory effect. While further mechanistic investigation of Microbiot^® in neurodegenerative diseases is warranted, our results support the potential utility of probiotics in PD.

Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects. In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase–positive neurons in substantia nigra pars compacta and Iba-1–positive stained microglia in ipsilateral striatum were measured. In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase–positive cells in the substantia nigra pars compacta, and more ramified Iba-1⁺ cells by 3HPX compared with PX. The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.

Parkinson’s disease (PD) is an idiopathic and progressive neurodegenerative disease characterized by the loss of ~ 80% of dopaminergic neurons in substantia nigra pars compacta (SNpc). Because activation of the innate cellular immune response, mediated by microglia, has been linked to the neurodegeneration in PD, in the present study, we evaluated the effects of lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) on microglia’s morphology, reflective of their activity, as well as tyrosine hydroxylase (TH)-positive neurons in SNpc and motor behavior. Adult male Wistar rats were stereotactically injected with LPS or 6-OHDA into the left dorsolateral striatum. Control groups received appropriate vehicle. The morphological changes of microglial cells and neurotoxic effects were examined at 1, 7, and 14 post-injection days. Both LPS and 6-OHDA caused activation and morphological changes in microglial cells as well as loss of dopaminergic neurons in SNpc. These effects were maximal at 14 days post-injection where motor impairments were also evident. However, our findings indicate that 6-OHDA causes a low degree of microglia activation compared to LPS. Hence, it may be concluded that LPS model of PD might be a better representation of inflammatory involvement in this devastating disease.