Irving Parra

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.

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.

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.

Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson’s disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. The purpose of this study was to gain some understanding of the actions of each drug, including potential antioxidant and anti-inflammatory effects and importantly, to determine whether the combination of the two drugs would be superior to each alone. Adult male Wistar rats were administered 6-OHDA into the dorso­lateral striatum, and the effects of Hc-TeTx fragment (20 μg/kg i.m. every 24 h) for 3 days; PPX (1 mg/kg p.o., every 12 h) for 30 days and their combination on various motor and neurochemical parameters were evaluated. Behavioral tests were carried out at 15 and 30 days post-treatments. At day 31, the animals were sacrificed and the levels of tyrosine hydroxylase (TH), reflecting dopaminergic activity in both striatum and substantia nigra, were evaluated. In addition, indices of astrogliosis, microgliosis, as well as oxidative stress in the striatum were determined. Both Hc-TeTx and PPX ameliorated the motor and neurochemical deficits induced by 6-OHDA lesion; however, the combination of the two drugs was not superior to each alone. Hence, at concentrations used in this study, no significant advantage in combining Hc-TeTx with PPX was noted. Although the results suggest similar neurochemical effects of the two compounds, further evaluation of different concentrations of Hc-TeTx and PPX as potential intervention in PD is warranted.