Neuronal Apoptosis: Pathological Basis of Behavioral Dysfunctions Induced by Angiostrongylus cantonensis in Rodents Model

Abstract

Angiostrongylus cantonensis invades the central nervous system (CNS) of humans to induce eosinophilic meningitis and meningoencephalitis and leads to persistent headache, cognitive dysfunction, and ataxic gait. Infected mice (nonpermissive host), admittedly, suffer more serious pathological injuries than rats (permissive host). However, the pathological basis of these manifestations is incompletely elucidated. In this study, the behavioral test, histological and immunohistochemical techniques, and analysis of apoptotic gene expression, especially caspase-3, were conducted. The movement and motor coordination were investigated at week 2 post infection (PI) and week 3 PI in mice and rats, respectively. The cognitive impairs could be found in mice at week 2 PI but not in rats. The plaque-like lesion, perivascular cuffing of inflammatory cells, and dilated vessels within the cerebral cortex and hippocampus were more serious in mice than in rats at week 3 PI. Transcriptomic analysis showed activated extrinsic apoptotic pathway through increased expression of TNFR1 and caspase-8 in mice CNS. Immunohistochemical and double-labeling for NeuN and caspase-3 indicated the dramatically increased expression of caspase-3 in neuron of the cerebral cortex and hippocampus in mice but not in rats. Furthermore, western-blotting results showed high expression of cleaved caspase-3 proteins in mice but relatively low expression in rats. Thus, extrinsic apoptotic pathway participated in neuronal apoptosis might be the pathological basis of distinct behavioral dysfunctions in rodents with A. cantonensis infection. It provides the evidences of a primary molecular mechanism for the behavioral dysfunction and paves the ways to clinical diagnosis and therapy for A. cantonensis infection.

Apoptosis and necroptosis of mouse hippocampal and parenchymal astrocytes, microglia and neurons caused by Angiostrongylus cantonensis infection

“…The tracks and microcavities caused by the migration of larvae in the brains of infected animals, as described in previous studies [ 21 ], cannot explain all the clinical neurological injuries in the hosts [ 20 ] or the distinct outcomes between permissive and non-permissive hosts after A. cantonensis infection since the same physical destruction of neural tissue caused by the migration of larvae can be seen within both of their brains [ 11 ]. Interestingly, our previous [ 22 ] and the current findings indicate the obvious apoptosis and necroptosis of parenchymal and hippocampal astrocytes, neurons and microglia of mice infected with A. cantonensis (Figs. 3 – 10 ), which might provide new insights into the pathogenesis of neuroangiostrongyliasis.…”

Trichostatin A, a Histone Deacetylase Inhibitor, Alleviates Eosinophilic Meningitis Induced by Angiostrongylus cantonensis Infection in Mice

“…Clinical exploration and animal studies confirmed that A. cantonensis invading the central nervous system caused neurological manifestations with behavioral dysfunctions (Hidelaratchi et al, 2005; Luo et al, 2017; Mengying et al, 2017). In the current study, we clearly elucidated that A. cantonensis infected mice exhibited dysfunctions of movement and cognition in a water maze task.…”

“…Eosinophilic meningitis in mice induced by A. cantonensis is characterized by infiltration of eosinophil and inflammatory cells and neuronal apoptosis (Luo et al, 2017). HDACi has long been used to treat neurodegenerative diseases (Hahnen et al, 2008).…”

“…The main pathological characteristic induced by A. cantonensis is eosinophilic meningitisis hemorrhage, vascular dilatation, focal necrosis with neuronal loss, and infiltration of inflammatory cells in brain parenchyma (OuYang et al, 2012). Our previous study showed that neuronal apoptosis might be the pathological basis of behavioral dysfunctions in rodents with A. cantonensis infection (Luo et al, 2017). In patients with angiostrongyliasis, neurological defects with persistent headache, paresthesia or hyperesthesia, nuchal rigidity, seizure, cognitive dysfunction, ataxic gait, and even unconsciousness after anthelmintic treatment are still common (Hidelaratchi et al, 2005).…”

Necroptosis and Caspase-2-Mediated Apoptosis of Astrocytes and Neurons, but Not Microglia, of Rat Hippocampus and Parenchyma Caused by Angiostrongylus cantonensis Infection

“…The pathogenic mechanisms involved in CNS parasitic infections consist of direct damage caused by the proliferation of protozoan parasites (Schluter and Barragan, 2019) and the physical disruption of tissue by migrating worms (Finsterer and Auer, 2013), while indirect injuries include alterations in the immune status of the CNS (Parlog et al, 2015), the modification of the function and structure of infected cells and the induction of programed cell death of host cells (Zhang et al, 2014;Halonen, 2015;Eugenin et al, 2019). Our previous studies indicated that apoptosis and necroptosis clearly occur in the hippocampal and parenchymal neurons, astrocytes and microglia of infected mice (Luo et al, 2017;Zhang et al, 2017). To further reveal the pathogenesis in permissive hosts infected with A. cantonensis, RT-qPCR, western blot analysis and immunofluorescence (IF) were applied to determine apoptosis, necroptosis, autophagy, and pyroptosis levels in the hippocampus and parenchyma of the rats.…”