The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis

Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma

Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies. Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury. We assessed retinal tissues using immunofluorescence for glial fibrillary acidic protein, microglia-specific proteins Iba1 and CD68, and phosphorylated tau (AT-270 pThr181 and AT-180 pThr231). Primary blast wave pressure resulted in activation of Müller glia, loss of photoreceptor cells, and an increase in phosphorylated tau in retinal neurons and glia. We found that 300-kPa blasts yielded no detectable cognitive or motor deficits, and no neurochemical or biochemical evidence of injury in the striatum or prefrontal cortex, respectively. These changes were detected 30 days after blast exposure, suggesting the possibility of long-lasting retinal injury and neuronal inflammation after primary blast exposure

Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases

Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics is immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. From the Clinical Editor Many nervous system disorders remain unresolved clinical problems. In many cases, drug agents simply cannot cross the blood-brain barrier (BBB) into the nervous system. The advent of nanomedicines can enhance the delivery of biologically active molecules for targeted therapy and imaging. This review focused on the use of nanotechnology for degenerative, inflammatory, and infectious diseases in the nervous system

Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice

Aims: Parkinson\u27s disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Results: Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048–1066

The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis.</p

The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis.</p

The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis.</p

The effect of intestinal inflammation and enteric nervous system deregulation in the pathogenesis of Parkinsonian syndrome

Increasing evidence from epidemiological studies, retrospective studies, clinical observations as well as pre-clinical in-vitro and in-vivo data suggest that Parkinson’s disease involves both the enteric and central nervous system. Notably intestinal dysfunction along with anosmia is one of the most common symptoms observed even decades before PD diagnosis. In order to understand how intestinal inflammation affects the enteric nervous system in the context of PD, we conducted multiple studies including a transgenic mouse model of PD (MitoPark), a mouse model of chronic exposure to environmental toxin manganese (Mn) as well as a known mouse model of intestinal inflammation-the dextran sodium sulfate (DSS) mouse model of colitis. PD and indeed many neurological disorders are gradually being recognized as multi-faceted maladies involving genetic predisposition and environmental triggers. Mn exposure has been implicated in environmentally-linked PD as evidenced by epidemiological studies done on humans exposed to Mn during mining, welding metals, and dry battery manufacturing. With the prevalence of high Mn content in the groundwater in many regions of US, we sought to elucidate the effect of chronic low-dose exposure to Mn on the GI tract. We found that Mn does affect the ENS, particularly the enteric glial cells (EGC) inducing mitochondrial dysfunction and ultimately cell death. In an in vivo model of chronic Mn exposure, we observed that even a low dose of Mn was sufficient to decrease GI motility, alter the gut microbiome population as well as GI metabolism. MitoPark mice that mimic the adult-onset and progressive nature of PD showed mild intestinal inflammation and spatial differences in gastrointestinal (GI) motility. Curiously, these mice have higher motility in the small intestine but lower in the large intestine. Moreover, exposure to an environmental toxin potentiated cell death in the colon with 12-week-old MitoPark having increased proapoptotic protein bax compared to non-exposed transgenic controls. In older MitoPark mice, the ENS showed presence of inflammation with increased expression of pro-inflammatory factors – inducible nitric oxide (iNOS) and tumor necrosis factor alpha (TNFα). We also found similar results in mice afflicted with DSS-induced colitis. These mice showed intestinal inflammation as well as immune cell infiltrations. Intriguingly, the lumbosacral region of the spinal cord and the substantia nigra region in the brain also showed higher proinflammatory (TNFα, iNOS and IL-1β) transcripts. Taken together, the data suggests that intestinal inflammation- caused either by a genetic predisposition or exposure to environmental toxin- can induce neurochemical changes in the ENS and consequently changes in the CNS via the gut-brain axis.</p

Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma

Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies. Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury. We assessed retinal tissues using immunofluorescence for glial fibrillary acidic protein, microglia-specific proteins Iba1 and CD68, and phosphorylated tau (AT-270 pThr181 and AT-180 pThr231). Primary blast wave pressure resulted in activation of Müller glia, loss of photoreceptor cells, and an increase in phosphorylated tau in retinal neurons and glia. We found that 300-kPa blasts yielded no detectable cognitive or motor deficits, and no neurochemical or biochemical evidence of injury in the striatum or prefrontal cortex, respectively. These changes were detected 30 days after blast exposure, suggesting the possibility of long-lasting retinal injury and neuronal inflammation after primary blast exposure.This article is published as Mammadova, Najiba, Shivani Ghaisas, Gary Zenitsky, Donald S. Sakaguchi, Anumantha G. Kanthasamy, Justin J. Greenlee, and M. Heather West Greenlee. "Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma." The American Journal of Pathology 187, no. 7 (2017): 1459-1472. DOI: 10.1016/j.ajpath.2017.03.005.</p