Alpha-synuclein (αS) is causally involved in the development of Parkinson disease (PD); however, its role in normal vertebrate physiology has remained unknown. Recent studies demonstrate that αS is ...induced by noroviral infection in the enteric nervous system of children and protects mice against lethal neurotropic viral infection. Additionally, αS is a potent chemotactic activator of phagocytes. In this report, using both wild-type and αS knockout mice, we show that αS is a critical mediator of inflammatory and immune responses. αS is required for the development of a normal inflammatory response to bacterial peptidoglycan introduced into the peritoneal cavity as well as antigen-specific and T cell responses following intraperitoneal immunization. Furthermore, we show that neural cells are the sources of αS required for immune competence. Our report supports the hypothesis that αS accumulates within the nervous system of PD individuals because of an inflammatory/immune response.
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•Peritoneal inflammation triggers αS production by neurons that innervate peritoneum•αS activates APCs by triggering TLR4 and promotes innate and adaptive immune responses•Neuronal αS is required for the induction of peritonitis and immune responses•αS-triggered immune responses may contribute to PD development and/or progression
Alam et al. show that αS produced by the neurons of the gastrointestinal system is critical for the manifestation of peritoneal inflammation and systemic antigen-specific immune responses, which may in turn, promote neuronal αS accumulation and contribute to the development and/or progression of Parkinson disease.
Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are ...implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract.
We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation.
We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation.
These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
The vagus nerve relays mood-altering signals originating in the gut lumen to the brain. In mice, an intact vagus is required to mediate the behavioural effects of both intraluminally applied ...selective serotonin reuptake inhibitors and a strain of Lactobacillus with antidepressant-like activity. Similarly, the prodepressant effect of lipopolysaccharide is vagus nerve dependent. Single vagal fibres are broadly tuned to respond by excitation to both anti- and prodepressant agents, but it remains unclear how neural responses encode behaviour-specific information. Here we demonstrate using ex vivo experiments that for single vagal fibres within the mesenteric neurovascular bundle supplying the mouse small intestine, a unique neural firing pattern code is common to both chemical and bacterial vagus-dependent antidepressant luminal stimuli. This code is qualitatively and statistically discernible from that evoked by lipopolysaccharide, a non-vagus-dependent antidepressant or control non-antidepressant Lactobacillus strain and are not affected by sex status. We found that all vagus dependent antidepressants evoked a decrease in mean spike interval, increase in spike burst duration, decrease in gap duration between bursts and increase in intra-burst spike intervals. Our results offer a novel neuronal electrical perspective as one explanation for mechanisms of action of gut-derived vagal dependent antidepressants. We expect that our ex vivo individual vagal fibre recording model will improve the design and operation of new, extant electroceutical vagal stimulation devices currently used to treat major depression. Furthermore, use of this vagal antidepressant code should provide a valuable screening tool for novel potential oral antidepressant candidates in preclinical animal models.
Vagus nerve signaling is a key component of the gut-brain axis and regulates diverse physiological processes that decline with age. Gut to brain vagus firing patterns are regulated by myenteric ...intrinsic primary afferent neuron (IPAN) to vagus neurotransmission. It remains unclear how IPANs or the afferent vagus age functionally. Here we identified a distinct ageing code in gut to brain neurotransmission defined by consistent differences in firing rates, burst durations, interburst and intraburst firing intervals of IPANs and the vagus, when comparing young and aged neurons. The aminosterol squalamine changed aged neurons firing patterns to a young phenotype. In contrast to young neurons, sertraline failed to increase firing rates in the aged vagus whereas squalamine was effective. These results may have implications for improved treatments involving pharmacological and electrical stimulation of the vagus for age-related mood and other disorders. For example, oral squalamine might be substituted for or added to sertraline for the aged.
...therapeutic hypothermia decreases metabolic demand in the myocardium at risk.  Weight (kg) Blood pH Before CPR Blood pH After CPR Arterial PaO2 Before CPR (mm Hg) Arterial PaO2 After CPR (mm Hg) ...CPR Duration (s)  CPP Before Initial ES (mm Hg) No. of ES Initial ES Success (%) Total ES Success (%) Epinephrine (μg/kg) NDS at 48 h After ROSC  Baseline PR 1 h PR 2 h PR 3 h PR 4 h PR 96 h Hypothermia (n = 8) 40.5(39-41) 7.53(7.47-7.57) 7.42(7.33-7.47) 99(94-116) 458(249-514) 350(321-437)* Control (n = 8) 40.5(39-45) 7.51(7.43-7.56) 7.35(7.19-7.47) 97(88-135) 386(237-487) 568(294-909) Hypothermia (n = 8) 18.4(11.3-36.4) 9.5(2-14) 75 97(60-100)* 30(30)* 0(0-75)* Control (n = 8) 17.6(10.0-28.4) 16.5(2-28) 38 70(33-94) 60(30-120) 400(0-400) Cardiac output (l/min)       Hypothermia (n = 8) 7.2(6.3-11.0) 5.2(2.6-7.7) 4.6(2.8-6.9) 4.6(2.6-5.7) 4.5(2.3-6.1) NA Control (n = 8) 6.61(4.0-9.4) 5.3(3.0-7.3) 4.8(3.8-6.7) 5.4(3.4-7.2) 4.9(3.8-12.2) NA LVEF (%)       Hypothermia (n = 8) 65.4(59.1-69.4) 56.7(50.6-60.9)* 60.4(54.4-68.9)* 62.6(54.7-69)* 63.3(59.7-67.1)dagger 65.4(62.5-68.5)* Control (n = 8) 64(56.7-68.2) 50.7(42-53.1) 50.9(40.8-54.8) 51.4(39.8-56.2) 52.9(41.2-55) 57.6(56.5-58.7) Fractional area change (%) Hypothermia (n = 8) 50.0(44.6-56.0) 41.9(35.0-45.6)* 44.5(36.6-54.8)* 48.1(40.6-54.0) 48.6(45.2-52.7) 49.6(44.4-52.6)* Control (n = 8) 49.1(43.6-54.4) 40.0(24.5-37.9) 32.3(23.5-40.7) 36.7(25.1-39.2)dagger 36.7(29.4-41.7)dagger 39.9(39.3-40.6) Isovolumetric relaxation time (s)       Hypothermia (n = 8) 1.0(0.9-1.2) 0.7(0.6-1.3)* 1.0(0.8-1.4)dagger 1.1(1.1-1.2)dagger 1.2(1.1-1.2)dagger 1.1(1.0-1.2)* Control (n = 8) 1.1(0.9-1.2) 0.6(0.4-0.7) 0.6(0.5-0.8) 0.6(0.6-0.7) 0.7(0.6-0.8) 0.8(0.7-0.9) E/E'       Hypothermia (n = 8) 10.1(7.2-10.7) 12.0(10.7-14.8) 9.1(8.2-10.0)* 9.1(7.6-9.7)* 8.7(8.0-9.9)* 8.9(7.2-10.4) Control (n = 8) 10.4(9.0-11.0) 12.8(11.7-16.2) 11.7(10.3-14.4) 11.3(10.1-13) 10.2(10.0-10.5) 11.5(10.0-13.1) Table 1 Comparison of Events and Measurements in Each Group Continuous variables are presented as median and range.CPP = coronary perfusion pressure; CPR = cardiopulmonary resuscitation; E/E' = spectral tissue Doppler echocardiography ratio; ES = electric shock; LVEF = left ventricular ejection fraction; NDS = neurological deficit score; PaO2 = partial pressure of oxygen in arterial blood; PC = precordial compression; PR = post-resuscitation; ROSC = return of spontaneous circulation.
Covering: 1993 to 2021 (mainly 2017-2021)Alzheimer's and Parkinson's diseases are neurodegenerative conditions affecting over 50 million people worldwide. Since these disorders are still largely ...intractable pharmacologically, discovering effective treatments is of great urgency and importance. These conditions are characteristically associated with the aberrant deposition of proteinaceous aggregates in the brain, and with the formation of metastable intermediates known as protein misfolded oligomers that play a central role in their aetiology. In this Highlight article, we review the evidence at the physicochemical, cellular, animal model and clinical levels on how the natural products squalamine and trodusquemine offer promising opportunities for chronic treatments for these progressive conditions by preventing both the formation of neurotoxic oligomers and their interaction with cell membranes.
Trodusquemine is an amphipathic aminosterol that has recently shown therapeutic benefit in neurodegenerative diseases altering the binding of misfolded proteins to the cell membrane. To unravel the ...underlying mechanism, we studied the interactions between Trodusquemine (TRO) and lipid monolayers simulating the outer layer of the plasma membrane. We selected two different compositions of dioleoylphosphatidylcholine (DOPC), sphingomyelin (SM), cholesterol (Chol) and monosialotetrahexosylganglioside (GM1) lipid mixture mimicking either a lipid-raft containing membrane (Ld+So phases) or a single-phase disordered membrane (Ld phase). Surface pressure-area isotherms and surface compressional modulus-area combined with Brewster Angle Microscopy (BAM) provided the thermodynamic and morphological information on the lipid monolayer in the presence of increasing amounts of TRO in the monolayer. Experiments revealed that TRO forms stable spreading monolayers at the buffer-air interface where it undergoes multiple reversible phase transitions to bi- and tri-layers at the interface. When TRO was spread at the interface with the lipid mixtures, we found that it distributes in the lipid monolayer for both the selected lipid compositions, but a maximum TRO uptake in the rafts-containing monolayer was observed for a Lipid/TRO molar ratio equal to 3:2. Statistical analysis of BAM images revealed that TRO induces a decrease in the size of the condensed domains, an increase in their number and in the thickness mismatch between the Ld and So phase. Experiments and MD simulations converge to indicate that TRO adsorbs preferentially at the border of the So domains. Removal of GM1 from the lipid Ld+So mixture resulted in an even greater TRO-mediated reduction of the size of the So domains suggesting that the presence of GM1 hinders the localization of TRO at the So domains boundaries.
Taken together these observations suggest that Trodusquemine influences the organization of lipid rafts within the neuronal membrane in a dose-dependent manner whereas it evenly distributes in disordered expanded phases of the membrane model.
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•TRO affects the molecular distribution of lipids in Ld+So monolayers.•TRO localizes at the border of So domains due to hydrophobic interactions.•TRO reorganizes the So domains influencing their size, shape and density.•Experiments and MD simulations provide a similar Ld+So thickness mismatch.•The results rationalize the therapeutical action of TRO in neurodegenerations.
Hypothermia is neuroprotectant but currently available cooling methods are laborious, invasive, and require whole-body cooling. There is a need for less invasive cooling of the brain. This study was ...conducted to assess the safety and efficacy of temperature reduction of the RhinoChill transnasal cooling device.
We conducted a prospective single-arm safety and feasibility study of intubated patients for whom temperature reduction was indicated. After rhinoscopy, the device was activated for 1 hour. Brain, tympanic, and core temperatures along with vital signs and laboratory studies were recorded. All general and device-related adverse events were collected for the entire hypothermia treatment.
A total of 15 patients (mean age, 50.3 ± 17.1 years) were enrolled. Brain injury was caused by intracerebral hemorrhage, trauma, and ischemic stroke in equal numbers. Hypothermia was induced for fever control in 9 patients and for neuroprotection/intracranial pressure control in 6. Core temperature, brain temperature, and tympanic temperature were reduced an average of 1.1 ± 0.6°C (range, 0.3 to 2.1°C), 1.4 ± 0.4°C (range, 0.8 to 5.1°C), and 2.2 ± 2°C (range, 0.5 to 6.5°C), respectively. Only 2 patients did not achieve the goal of ≥1°C decrease in temperature. Brain temperature, tympanic temperature, and core temperature reductions were similar between the afebrile and febrile patients. There were no unanticipated adverse events and only 1 anticipated adverse event: hypertension in 1 subject that led to discontinuation of cooling after 30 minutes. There were no nasal complications.
Intranasal cooling with the RhinoChill device appears safe and effectively lowers brain and core temperatures. Further study is warranted to assess the efficacy of hypothermia through intranasal cooling for brain-injured patients.
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