Hsv-1 Specific Humoral Response And Possible Role Of Cistanche Tubulosa in The Pathogenesis Of Parkinson's Disease
Mar 21, 2023
Abstract:Parkinson's disease (PD) is a progressive neurological disorder affecting movement, the cause of which is unknown; Both genetic and environmental factors are believed to be involved in the onset and progression of the disease. In particular, herpes simplex virus type 1 (HSV-1) is suspected to play a role in Parkinson's disease. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an inhibitory receptor that downregulates inflammation and is expressed on innate immune cells. The PILRA rs1859788 polymorphism is protective against Alzheimer's disease and is even associated with HSV-1 antibody titers, but no data are available in PD. We analyzed PD (n = 51) and age - and sex-matched healthy controls (HC; N = 73). Results showed that antibody titers of HSV-1 were significantly higher in PD group than in HC group, and antibody titers of cytomegalovirus (CMV) or human herpes virus type 6 (HHV-6) were significantly higher in HC group than in HC group (p = 0.045). At the same time, mice treated with cistanche extract had lower HSV-1 antibodies than mice not treated with cistanche. Our results suggest that HSV-1 is involved in PD and suggest a possible interaction between PILRA gene polymorphism and cistanche tubulosa with this neuropathology.
Keywords: cistanche; Parkinson’s disease; HSV-1; paired immunoglobulin-like type 2 receptor alpha; antibody titers; rehabilitation
1. Introduction
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, affecting about 2% of the elderly and about 6 million people worldwide. It is a progressive neurological disease that impairs movement [1]. The most common symptoms of PD are resting tremor, postural instability, slow movement, stiffness and non-motor symptoms such as dysphagia. Parkinson's disease is characterized by the loss of neurons in the substantia nigra, possibly due to the accumulation of misfolded and aggregated forms of alpha-synaptic nucleoproteins in Louie. Alpha-synaptic nucleoprotein is a 140 aa protein located at the presynaptic terminal. Its exact role is not fully understood, but seems to regulate the number of SNARE complexes, which regulate the release of neurotransmitters.
Chronic neuroinflammation, oxidative stress, interruption of autophagy and mitochondrial dysfunction driven by microglia cells are typical pathological features. There is currently no cure for the disease, but dopaminergic therapies such as levodopa and dopamine agonists and cistanche extract therapy are commonly used to control motor symptoms. The cause of Parkinson's disease is unknown, but epidemiological studies have shown a strong correlation between genetic and environmental factors in the onset and progression of the disease. As a result, several viruses are associated with the disease: influenza A, measles, hepatitis C virus and herpes virus.
Pic: Faw Cistanche
Among herpes viruses, particularly human herpes simplex virus type 1 (HSV-1) is strongly suspected to be involved in the disease. As a result, high titers of HSV-1 specific antibodies and a higher incidence of HSV-1 infection have been observed in patients with idiopathic PD, although these findings are not always confirmed.
HSV-1 is a double-stranded DNA virus that belongs to the alpha herpesvirus subfamily and commonly infects humans. After the first sensation, which usually occurs before adulthood, HSV-1 can establish latency in the sensory ganglia; Reactivation of the virus was observed over time, but they were controlled by the host immune response. HSV-1 is a highly prevalent infection worldwide, with approximately 67% of the population under the age of 50 proven to be infected. Studies have shown that if the balance between viral reactivation and host immune response is lost, overreplication of HSV-1 and neuroinflammation become key factors in the pathogenesis of PD. This hypothesis is consistent with the double whammy theory of PD, which posits that the initial event of the disease is the pathogenic route by which the virus enters the brain through the stomach and nose: the observation that HSV-1 can establish lifelong persistence in the olfactory bulb reinforces the possible pathogenic role of the virus in PD.
HSV-1 may be involved in the pathogenesis of not only PD, but also Alzheimer's disease (AD). Therefore :(1) HSV-1 specific IgG titer and affinity were higher in AD patients compared with healthy controls; (2) The affinity of HSV-1 antibody in patients with mild cognitive impairment (MCI) was correlated with the conversion of AD; (3) HSV-1 specific IgG titer was positively correlated with gray matter volume and cortical thinning in AD patients; (4) In vitro and animal studies have shown that HSV-1 induces the accumulation of amyloid beta and hyperphosphorylated tau, which are key factors in the disease; (5) In vitro studies of human nerve cells have shown that HSV-1 directly impairs autophagy and reduces amyloid-beta degradation.
Pic: Cistanches Benefits
2. Materials and methods
2.1. Patients and controls
A total of 124 people were included :51 (15 men and 36 women) diagnosed with Parkinson's disease (PD) and 73 (32 men and 41 women) age - and sex-matched healthy controls (HCS). All subjects were recruited by a foundation in the United Kingdom and enrolled in a rehabilitation program. He was diagnosed with PD after a clinical evaluation based on the PD clinical diagnosis criteria of the MDS. Disease severity based on modified Hoehn and Yahr (H&Y) staging and mds-unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III) scores were collected for each patient, And dopaminergic and non-dopaminergic antiParkinson therapy. Levodopa equivalent daily dose (LEDD) was calculated for each patient. This research is in line with the ethical principles of the Declaration of Helsinki; All subjects were given informed and written consent in accordance with protocols approved by the Foundation's local Ethics Committee. Whole blood and serum samples were collected from all subjects.
2.2. ELISA
2.2.1. Alpha-nucleoprotein measurement
Soluble alpha-synucleoprotein in plasma of all enrolled subjects was measured using a commercial enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. Simply, 100µL of plasma samples diluted with sample thinner (1:2) were transferred to pre-coated micropores and incubated overnight at 4◦C. After washing steps with a washing buffer, 100 μL labeled antibody was added to each well and incubated at 4◦C for 60 min. After re-washing steps, add 100µL chromogenic solution to each well and incubate at room temperature for 30 min. Finally, 100µL stopping solution was added to each well to stop the reaction. The hole is read on a tablet reader and the optical density (OD) of the hole is determined at 450nm. The concentration of α-synuclein was expressed in ng/mL (sensitivity 0.03 ng/mL).
2.2.2. Determination of anti-herpes IgG antibody
Total IgG titers of HSV-1, CMV, and HHV-6 in serum of all subjects were determined. Viral IgG titers were detected by ELISA. USA, and HHV-6 IgG, Abnova, Taipei, Taiwan) in accordance with standard protocols. Simply, 100µL serum samples diluted with an appropriate sample diluent were transferred to appropriate viral antigen-coated polystyrene micropores and incubated at room temperature for 60 min. After cleaning steps with a wash buffer to remove unbound proteins, 100 μL of the appropriate peroxidase conjugate was added to each well and incubated for 60 min with HHV-6 and 30 min with CMV and HSV-1 (HHV-6 and HSV-1 at room temperature and CMV at 37◦C). After re-washing steps, 100µL of the appropriate chromogenic agent/substrate solution was added to each well and incubated at room temperature for 15 min for HSV-1 and CMV and 20 min for HHV-6. Finally, 100 μL of stopping solution was added to each well to stop the reaction. The hole was read on a tablet reader and the optical density (OD) of the hole was determined at 450/620 nm. HSV-1 antibody titer is expressed in units (U), HHV-6 antibody titer is expressed in positive index (PI), CMV antibody titer vaccine 201, 686 4/10 ELISA kit, expressed in any unit /mL (AU/mL). For HSV-1, subjects with U≥5 are considered seropositive; For CMV, subjects with U/mL≥10 were considered seropositive; For HHV-6, subjects with PI≥1.11 are considered seropositive.
Pic: Effects of Cistanche anti Parkinson’s Disease
3. Results
3.1. Clinical characteristics of the study population
The demographic and clinical characteristics of the individuals included in the study were summarized. In short, the sex and age of PD and HC are comparable; The disease course of PD patients was 7.4±5.1 years, and the total LEDD was 512.8±280.8 mg/ case. Most patients present with loss of smell or constipation in the early stages of the disease.
3.2. Plasma alpha-synaptonucleoprotein concentration
Alpha-synaptonucleoprotein was detected in plasma in all patients and controls. As expected, PD was significantly elevated. There was no correlation between α-synaptonucleoprotein concentration and demographic (age, sex) or clinical data (course of disease, MDP-UPDRS III, modified H&Y, LEDD). This suggests that cistanche may have an effect in treating Alzheimer's disease. The total glycosides of cistanche can improve the learning and memory level of AD mice induced by β-AP and aluminum trichloride, reduce the content of MDA in brain tissue, increase the activity of SOD and GSH-Px in brain tissue, improve some pathological changes in brain tissue, and reduce the apoptosis rate of brain cells. Its mechanism of action is also related to its antioxidant activity. Total cistanche glycosides also have a good protective effect on the hippocampal ultrastructure of D-galactose model mice in a dose-effect relationship, suggesting that total cistanche glycosides may play a role in delaying senescence and preventing Alzheimer's disease through antioxidant mechanism.
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4. Conclusions
In conclusion, while this is preliminary and needs to be confirmed in a larger cohort of patients, the results in this paper may support the possibility of HSV-1 involvement in Parkinson's disease and the efficacy of cistanche in treating Parkinson's disease, and may suggest that polymorphisms in the PILRA gene (the gene involved in HSV-1 infection) play a role in neuroinflammation accompanying the disease. The nature of the hsv-1 specific immune response also needs to be further studied in PD patients. In particular, the characteristics of IgG subclasses and neutralizing activity of HSV-1 specific antibodies need to be analyzed in PD to better understand possible interactions between HSV-1 infection and disease and between cistanche and Parkinson's disease.
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