Huntington's Disease Symptoms Research Articles

Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by preferential loss of neurons in the striatum in patients, which leads to motor and cognitive impairments and death that often occurs 10-15 years after the onset of symptoms. The expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (HTT) has been defined as the cause of HD, but the mechanism underlying neuronal death remains unclear. Multiple mechanisms, including inflammation, may jointly contribute to HD pathogenesis. Altered inflammation response is evident even before the onset of classical symptoms of HD. In this review, we summarize the current evidence on immune and inflammatory changes, from HD animal models to clinical phenomenon of patients with HD. The understanding of the impact of inflammation on HD would help develop novel strategies to treat HD.

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that occurs worldwide. Despite some progress in understanding the onset of HD, drugs that block or delay symptoms are still not available. In recent years, many treatments have been proposed; among them, nuclear transcriptional factor-2 (Nrf2) enhancer compounds have been proposed as potential therapeutic agents to treat HD. Nrf2 triggers an endogenous antioxidant pathway activated in different neurodegenerative disorders. Probably, the stimulation of Nrf2 during either the early phase or before HD symptoms' onset, could slow or prevent striatum degeneration. In this review, we present the scientific literature supporting the role of Nrf2 in HD and the potential prophylactic and therapeutic role of this compound.

Calcium imaging: A versatile tool to examine Huntington's disease mechanisms and progression.

Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that causes chorea, cognitive deficits, and psychiatric symptoms. It is characterized by accumulation of mutant Htt protein, which primarily impacts striatal medium-sized spiny neurons (MSNs), as well as cortical pyramidal neurons (CPNs), causing synapse loss and eventually cell death. Perturbed Ca2+ homeostasis is believed to play a major role in HD, as altered Ca2+ homeostasis often precedes striatal dysfunction and manifestation of HD symptoms. In addition, dysregulation of Ca2+ can cause morphological and functional changes in MSNs and CPNs. Therefore, Ca2+ imaging techniques have the potential of visualizing changes in Ca2+ dynamics and neuronal activity in HD animal models. This minireview focuses on studies using diverse Ca2+ imaging techniques, including two-photon microscopy, fiber photometry, and miniscopes, in combination of Ca2+ indicators to monitor activity of neurons in HD models as the disease progresses. We then discuss the future applications of Ca2+ imaging to visualize disease mechanisms and alterations associated with HD, as well as studies showing how, as a proof-of-concept, Ca2+imaging using miniscopes in freely-behaving animals can help elucidate the differential role of direct and indirect pathway MSNs in HD symptoms.

Postnatal Foxp2 regulates early psychiatric-like phenotypes and associated molecular alterations in the R6/1 transgenic mouse model of Huntington's disease

Huntington's Disease (HD) is a devastating disorder characterized by a triad of motor, psychiatric and cognitive manifestations. Psychiatric and emotional symptoms appear at early stages of the disease which are consistently described by patients and caregivers among the most disabling. Here, we show for the first time that Foxp2 is strongly associated with some psychiatric-like disturbances in the R6/1 mouse model of HD. First, 4-week-old (juvenile) R6/1 mice behavioral phenotype was characterized by an increased impulsive-like behavior and less aggressive-like behavior. In this line, we identified an early striatal downregulation of Foxp2 protein starting as soon as at postnatal day 15 that could explain such deficiencies. Interestingly, the rescue of striatal Foxp2 levels from postnatal stages completely reverted the impulsivity-phenotype and partially the social impairments concomitant with a rescue of dendritic spine pathology. A mass spectrometry study indicated that the rescue of spine loss was associated with an improvement of several altered proteins related with cytoskeleton dynamics. Finally, we reproduced and mimicked the impulsivity and social deficits in wild type mice by reducing their striatal Foxp2 expression from postnatal stages. Overall, these results imply that early postnatal reduction of Foxp2 might contribute to the appearance of some of the early psychiatric symptoms in HD.

Huntingtin coordinates dendritic spine morphology and function through cofilin-mediated control of the actin cytoskeleton.

Compelling evidence indicates that in Huntington's disease (HD), mutation of huntingtin (HTT) alters several aspects of early brain development such as synaptogenesis. It is not clear to what extent the partial loss of wild-type HTT function contributes to these abnormalities. Here we investigate the function of HTT in the formation of spines. Although larger spines normally correlate with more synaptic activity, cell-autonomous depletion of HTT leads to enlarged spines but reduced excitatory synaptic function. We find that HTT is required for the proper turnover of endogenous actin and to recruit AMPA receptors at active synapses; loss of HTT leads to LIM kinase (LIMK) hyperactivation, which maintains cofilin in its inactive state. HTT therefore influences actin dynamics through the LIMK-cofilin pathway. Loss of HTT uncouples spine structure from synaptic function, which may contribute to the ultimate development of HD symptoms.

A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study.

BackgroundRemote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring.ObjectiveThe aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD.MethodsThis analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts—the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic.ResultsParticipants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90).ConclusionsThese results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.

Spermatozoan Metabolism as a Non-Traditional Model for the Study of Huntington's Disease.

Huntington’s Disease (HD) is a fatal autosomal dominant neurodegenerative disease manifested through motor dysfunction and cognitive deficits. Decreased fertility is also observed in HD animal models and HD male patients, due to altered spermatogenesis and sperm function, thus resulting in reduced fertilization potential. Although some pharmaceuticals are currently utilized to mitigate HD symptoms, an effective treatment that remedies the pathogenesis of the disease is yet to be approved by the FDA. Identification of genes and relevant diagnostic biomarkers and therapeutic target pathways including glycolysis and mitochondrial complex-I-dependent respiration may be advantageous for early diagnosis, management, and treatment of the disease. This review addresses the HD pathway in neuronal and sperm metabolism, including relevant gene and protein expression in both neurons and spermatozoa, indicated in the pathogenesis of HD. Furthermore, zinc-containing and zinc-interacting proteins regulate and/or are regulated by zinc ion homeostasis in both neurons and spermatozoa. Therefore, this review also aims to explore the comparative role of zinc in both neuronal and sperm function. Ongoing studies aim to characterize the products of genes implicated in HD pathogenesis that are expressed in both neurons and spermatozoa to facilitate studies of future treatment avenues in HD and HD-related male infertility. The emerging link between zinc homeostasis and the HD pathway could lead to new treatments and diagnostic methods linking genetic sperm defects with somatic comorbidities.

Neuroprotective effect of CTK 01512-2 recombinant toxin at the spinal cord in a model of Huntington's disease.

What is the central question of this study? We investigated the effects of intrathecal administration of a novel toxin, CTK 01512-2, in a mouse model of Huntington's disease. We asked whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high-risk brain intervention. What is the main finding and its importance? We provided evidence of a novel, local, neuroprotective effect of CTK 01512-2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain. Phα1β is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.

The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.

Huntington’s disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes.

Retinoic acid receptor beta protects striatopallidal medium spiny neurons from mitochondrial dysfunction and neurodegeneration.

Retinoic acid is a powerful regulator of brain development, however its postnatal functions only start to be elucidated. We show that retinoic acid receptor beta (RARβ), is involved in neuroprotection of striatopallidal medium spiny neurons (spMSNs), the cell type affected in different neuropsychiatric disorders and particularly prone to degenerate in Huntington disease (HD). Accordingly, the number of spMSNs was reduced in the striatum of adult Rarβ-/- mice, which may result from mitochondrial dysfunction and neurodegeneration. Mitochondria morphology was abnormal in mutant mice whereas in cultured striatal Rarβ-/- neurons mitochondria displayed exacerbated depolarization, and fragmentation followed by cell death in response to glutamate or thapsigargin-induced calcium increase. In vivo, Rarβ-/- spMSNs were also more vulnerable to the mitochondrial toxin 3-nitropropionic acid (3NP), known to induce HD symptoms in human and rodents. In contrary, an RARβ agonist, AC261066, decreased glutamate-induced toxicity in primary striatal neurons in vitro, and diminished mitochondrial dysfunction, spMSN cell death and motor deficits induced in wild type mice by 3NP. We demonstrate that the striatopallidal pathway is compromised in Rarβ-/- mice and associated with HD-like motor abnormalities. Importantly, similar motor abnormalities and selective reduction of spMSNs were induced by striatal or spMSN-specific inactivation of RARβ, further supporting a neuroprotective role of RARβ in postnatal striatum.

Negative symptoms in Huntington's disease.

Apathy is the commonest psychiatric manifestation in Huntington's disease (HD). We investigated negative psychiatric symptoms-as determined by the Scale for the Assessment of Negative Psychiatric Symptoms (SANS)-in early and intermediate HD patients, hypothesizing that such symptoms would be prominent and constitute a more comprehensive and clinically relevant assessment than apathy alone. We also assessed relations between negative symptoms and disease stage, mood, motor, and cognitive disturbances. Thirty-five stage 1 and twenty-nine stage 2 consecutive adult HD outpatients were administered SANS; the Scale for the Assessment of Positive Psychiatric Symptoms (SAPS); the motor section of the Unified Huntington's Disease Rating Scale (UHDRS); Total Functional Capacity (TFC); and instruments to assess cognition, anxiety, and depression. The groups had similar age, education, and CAG length. Scores on the Hamilton depression and anxiety scales, and SAPS were similar. Negative symptoms were pervasive in the entire series. Illness duration, UHDRS, TFC, cognition, and SANS scores were significantly worse in stage 2. Mini Mental State Examination (MMSE) and SAPS scores were significantly (multiple regression) associated with SANS score, while Hamilton depression and UHDRS scores were not. SANS score was also associated with stage after removing the cognition-related domains of alogia and attention. Negative symptoms are pervasive in HD but more severe in stage 2. The associations of SANS with MMSE and SAPS suggest impaired cognition and thinking as important in generating negative symptoms. SANS appears useful for revealing a wide range of negative symptoms in HD.

Nanotechnology in Improving the Treatment of Huntington's Disease: a Systematic Review.

Huntington's disease (HD) is a degenerative genetic condition characterized by cognitive, motor, and psychiatric disturbance. It is caused by a dominantly inherited alteration in the huntingtin gene. Even though symptomatic management is the mainstay of HD treatment, in the thesis, one of the leading causes of the low success of current therapy is their low efficacy for crossing the blood-brain barrier (BBB). The improvement in drug delivery through the BBB may be achieved by some endogenous uptake mechanisms and nanocarrier systems, increasing the bioavailability and slow-release of macromolecular drugs in the central nervous system. In the present study, we present state-of-the-art scientific production on nanotechnology in the treatment of HD symptoms. Here, we discussed the benefits of nanotechnology pharmacological therapy tested in rodent animal models and in vitro specific analyses. We presented why we could apply nanotechnology to improve the transport of drugs through BBB based on already postulated hypotheses about potential pharmacological therapy against some HD symptoms.

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease.

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

Subdural Hematoma as a Serious Complication of Huntington's Disease: An Observational Study.

Persons with Huntington's disease (HD) are at increased risk for subdural hematomas (SDH) because of underlying brain atrophy and increased frequency of falls and head trauma. SDH can cause serious disability, but there is little information about the association of SDH with HD in the medical literature. To review the occurrence and characteristics of SDH seen in clinics specializing in HD. A retrospective review identifying the occurrence and manifestations of SDH in HD patients attending three HDSA Centers of Excellence. Twenty-five HD patients (16F/9M) were identified with SDH. Twelve (44%) SDH were bilateral, 16 (60%) required surgical intervention, and 2 resulted in death. Mean age at the time of SDH was 60 years, mean duration of HD symptoms prior to event was 8 years, mean CAG repeat expansion size was 43 and mean UHDRS motor score obtained closest to time of SDH was 51 (16 patients). Most SDH occurred in the context of ground level falls or using stairs although 5 patients had no history of head trauma. Additional brain injury may occur along with the SDH. The most common symptoms were altered mental status, hemiparesis and loss of consciousness. The over-representation of females in this study requires replication and further investigation. Patients with HD are at increased risk for SDH. An increased suspicion for SDH in HD patients should be considered, as this phenomenon may be initially unrecognized, may require extensive utilization of medical resources and is a potential cause of death.

Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease.

Mitochondrial dysfunction is associated with neuronal damage in Huntington's disease (HD), but the precise mechanism of mitochondria-dependent pathogenesis is not understood yet. Herein, we found that colocalization of XIAP and p53 was prominent in the cytosolic compartments of normal subjects but reduced in HD patients and HD transgenic animal models. Overexpression of mutant Huntingtin (mHTT) reduced XIAP levels and elevated mitochondrial localization of p53 in striatal cells in vitro and in vivo. Interestingly, XIAP interacted directly with the C-terminal domain of p53 and decreased its stability via autophagy. Overexpression of XIAP prevented mitochondrially targeted-p53 (Mito-p53)-induced mitochondrial oxidative stress and striatal cell death, whereas, knockdown of XIAP exacerbated Mito-p53-induced neuronal damage in vitro. In vivo transduction of AAV-shRNA XIAP in the dorsal striatum induced rapid onset of disease and reduced the lifespan of HD transgenic (N171-82Q) mice compared to WT littermate mice. XIAP dysfunction led to ultrastructural changes of the mitochondrial cristae and nucleus morphology in striatal cells. Knockdown of XIAP exacerbated neuropathology and motor dysfunctions in N171-82Q mice. In contrast, XIAP overexpression improved neuropathology and motor behaviors in both AAV-mHTT-transduced mice and N171-82Q mice. Our data provides a molecular and pathological mechanism that deregulation of XIAP triggers mitochondria dysfunction and other neuropathological processes via the neurotoxic effect of p53 in HD. Together, the XIAP-p53 pathway is a novel pathological marker and can be a therapeutic target for improving the symptoms in HD.

Metabotropic Glutamate Receptor 2/3 Activation Improves Motor Performance and Reduces Pathology in Heterozygous zQ175 Huntington Disease Mice.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that leads to progressive motor impairments with no available disease-modifying treatment. Current evidence indicates that exacerbated postsynaptic glutamate signaling in the striatum plays a key role in the pathophysiology of HD. However, it remains unclear whether reducing glutamate release can be an effective approach to slow the progression of HD. Here, we show that the activation of metabotropic glutamate receptors 2 and 3 (mGluR2/3), which inhibit presynaptic glutamate release, improves HD symptoms and pathology in heterozygous zQ175 knockin mice. Treatment of both male and female zQ175 mice with the potent and selective mGluR2/3 agonist LY379268 for either 4 or 8 weeks improves both limb coordination and locomotor function in all mice. LY379268 also reduces mutant huntingtin aggregate formation, neuronal cell death, and microglial activation in the striatum of both male and female zQ175 mice. The reduction in mutant huntingtin aggregates correlates with the activation of a glycogen synthase kinase 3β-dependent autophagy pathway in male, but not female, zQ175 mice. Furthermore, LY379268 reduces both Akt and ERK1/2 phosphorylation in male zQ175 mice but increases both Akt and ERK1/2 phosphorylation in female zQ175 mice. Taken together, our results indicate that mGluR2/3 activation mitigates HD neuropathology in both male and female mice but is associated with the differential activation and inactivation of cell signaling pathways in heterozygous male and female zQ175 mice. This further highlights the need to take sex into consideration when developing future HD therapeutics. SIGNIFICANCE STATEMENT: The mGluR2/3 agonist LY379268 improves motor impairments and reduces pathology in male and female zQ175 Huntington's disease mice. The beneficial outcomes of LY379268 treatment in Huntington's disease mice were mediated by divergent cell signaling pathways in both sexes. We provide evidence that mGluR2/3 agonists can be repurposed for the treatment of Huntington's disease, and we emphasize the importance of investigating sex as a biological variable in preclinical disease-modifying studies.

Early impairment of thalamocortical circuit activity and coherence in a mouse model of Huntington's disease

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. There is no known cure for HD, but its progressive nature allows for early therapeutic intervention. Currently, much of the research has focused on the striatum, however, there is evidence suggesting that disruption of thalamocortical circuits could underlie some of the early symptoms of HD. Loss of both cortical pyramidal neurons (CPNs) and thalamic neurons occurs in HD patients, and cognitive, somatosensory, and attention deficits precede motor abnormalities. However, the role of thalamocortical pathways in HD progression has been understudied. Here, we measured single unit activity and local field potentials (LFPs) from electrode arrays implanted in the thalamus and primary motor cortex of 4–5 month-old male and female Q175 mice. We assessed neuronal activity under baseline conditions as well as during presentation of rewards delivered via actuation of an audible solenoid valve. HD mice showed a significantly delayed licking response to the reward stimulus. At the same time, neuronal activation to the reward was delayed in thalamic neurons, CPNs and fast-spiking cortical interneurons (FSIs) of HD mice. In addition, thalamocortical coherence increased at lower frequencies in HD relative to wildtype mice. Together, these data provide evidence that impaired cortical and thalamic responses to reward stimuli, and impaired thalamocortical coherence, may play an important early role in motor, cognitive, and learning deficits in HD patients.

Multimodal treatment strategies in Huntington’s disease

Huntington’s disease (HD) is an incurable neurodegenerative disease that causes involuntary movements, emotional lability, and cognitive dysfunction. HD symptoms usually develop between ages 30 and 50, but can appear as early as 2 or as late as 80 years. Currently no neuroprotective and neurorestorative interventions are available. Early multimodal intervention in HD is only possible if the genetic diagnosis is made early. Early intervention in HD is only possible if genetic diagnosis is made at the disease onset or when mild symptoms manifest. Growing evidence and understanding of HD pathomechanism has led researchers to new therapeutic targets. Here, in this article we will talk about the multimodal treatment strategies and recent advances made in this field which can be used to target the HD pathogenesis at its most proximal level.

The gut microbiome in Huntington disease: A review

Huntington's disease (HD) is a neurological disease caused by a trinucleotide repeat increase in the huntingtin (htt) gene, which is widely expressed in the brain and peripheral tissues. While many studies have focused on the cognitive, psychological, and motor symptoms of HD, however, the scope of peripheral pathology and its possible impact on central symptoms has received less attention. We hypothesised that because disruption of the gastrointestinal microbiota (gut dysbiosis) has lately been identified in a number of neurological and psychiatric illnesses, it might also occur in HD. In the HD gut microbiota, bacteriodetes increased whereas firmicutes decreased proportionally. Despite a larger food consumption, the gut dysbiosis was associated with a reduction in body weight growth. The presence of greater faecal water content in hd was also linked to a shift in the gut microenvironment. In this review, we present an update on the association between microbiome and brain function as it relates to huntington's disease.

Ellagic acid prevents 3-nitropropionic acid induced symptoms of Huntington's disease.

Mitochondrial abnormalities and redox imbalance are major pathogenic factors in progression of Huntington's disease (HD), manifested clinically by affective, motor, cognitive, and psychiatric incompetence. Antioxidants behold much promise in mitigation of several pathological facets in HD. Ellagic acid (EA) is a naturally derived polyphenol acknowledged for potent neuroprotective abilities that enabled its significance amongst popular brain tonics. The present study is aimed to examine the outcome of EA pre-treatment in 3-nitropropionic acid (3-NP) rat prototype of HD. Separate rat groups were pre-treated with EA (25, 50, and 100mg/kg, p.o.) for 21days and 3-NP (10mg/kg, i.p.) was given for 14days alongside to induce symptoms of HD. The physical/motor functions (narrow beam paradigm, footprint study, hanging-wire assessment) and cognitive abilities using elevated plus maze and novel object recognition task were evaluated. Entire brain was isolated and succinate dehydrogenase activity and parameters of oxido-nitrosative stress were assessed in mitochondrial fraction. 3-NP accrued oxido-nitrosative stress and significant decrease in succinate dehydrogenase activity caused motor and cognitive deficits in rats. EA pre-treatment resurrected succinate dehydrogenase activity in 3-NP treated rats that indicated preservation of mitochondrial function. A significant decrease in thiobarbituric acid reactive substances and nitrite levels and increase in glutathione and catalase activity by EA in 3-NP treated rats was noted. EA protected the rats against 3-NP triggered cognitive insufficiency and motor disturbances. It can be inferred that ellagic acid protects against 3-NP induced mitochondrial dysfunction and oxido-nitrosative stress in the brain. EA supplements or nutraceuticals might possess protective potential against symptoms of HD.