What Causes Seizures in Neurocysticercosis?

Neurocysticercosis (NCC) is the most prevalent parasitic infection of the central nervous system. It is caused by the presence of larvae of the cestode Taenia solium in the brain. The most common symptom of NCC is seizures, and it is widely considered the world's leading cause of preventable epilepsy. Despite the prevalence and impact of NCC, a thorough, mechanistic understanding of seizure generation is still lacking. In this review, we address the question "What causes seizures in NCC?" by summarizing and discussing the major theories that seek to explain the seizurogenic and epileptogenic processes in this disorder. In addition, we highlight the potential for recent advances in disease modeling to help accelerate progress in this area.

In vitro and in vivo anti-seizure activity of hydromethanolic extract and fractions of Pterolobium stellatum.

ETHNOPHARMACOLOGICAL RELEVANCE: In Ethiopia, the whole plant juice of Pterolobium stellatum is used to treat seizures and epilepsy. AIM OF THE STUDY: To investigate the antiseizure activity of hydromethanolic crude extract and fractions collected from leaves of P. stellatum using both in vitro, and in vivo seizure models in mice. MATERIALS AND METHODS: Fresh leaves of P. stellatum were collected from Awash Melka, Addis Ababa, Ethiopia. An 80% crude methanol extract was further fractionated to produce petroleum ether, chloroform, butanol, and aqueous fractions. Anti-seizure activity of the crude extract and fractions (petroleum ether, chloroform, butanol, and water) were assessed at a concentration of 0.7 mg/ml using the in vitro 0 Mg2+ model of seizures in mouse brain slices prepared from 14- to 21-day-old C57BL/6 mice. The maximal electroshock seizure (MES) model and the pentylenetetrazol (PTZ) seizure model for seizures were performed on male BALB/c mice using 400 mg/kg and 800 mg/kg of crude 80% methanol extract, as well as the four fractions described above. Diazepam and phenytoin were used as positive controls for PTZ and MES test respectively. RESULTS: Addition of 0.7 mg/ml of crude 80% methanol extract of P. stellatum prevented the onset of SLEs in most brain slices in the 0 Mg2+in vitro model of seizures, with similar efficacy to diazepam (3 µM). The same extract at 400 and 800 mg/kg was efficacious in reducing the hindlimb extension time in the MES model and delaying the onset of myoclonic convulsions in the PTZ model, although not to the same extent as phenytoin (10 mg/kg) or diazepam (5 mg/kg). The chloroform and water fractions of the crude extract also showed significant anti-seizure activity across all three models whilst the non-polar petroleum ether and butanol fractions did not. The UPLC-MS analysis indicated the presence of gallic acid, ellagic acid, kaempferol, myricitrin, isoquercitrin and quercitirin in the crude extract. Gallic acid and ellagic acid were observed in chloroform fraction and in the water fraction ellagic acid, kaempferol, myricitrin and isoquercitrin were detected. CONCLUSION: The crude hydromethanolic extract of P. stellatum has significant anti-seizure activity. The chloroform and aqueous fractions have antiseizure activity. The extracts have previously identified compounds with anticonvulsant activity which indicates the antiseizure potential of the plant.

Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability.

Many neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the "Inhibitory Level" (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses combines at an encircled branch junction. The extent of this inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This inhibitory accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising-but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to-but not at-a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- by loading that occurs when inhibitory synapses are co-located.

Neuroimmunology of Common Parasitic Infections in Africa.

Parasitic infections of the central nervous system are an important cause of morbidity and mortality in Africa. The neurological, cognitive, and psychiatric sequelae of these infections result from a complex interplay between the parasites and the host inflammatory response. Here we review some of the diseases caused by selected parasitic organisms known to infect the nervous system including Plasmodium falciparum, Toxoplasma gondii, Trypanosoma brucei spp., and Taenia solium species. For each parasite, we describe the geographical distribution, prevalence, life cycle, and typical clinical symptoms of infection and pathogenesis. We pay particular attention to how the parasites infect the brain and the interaction between each organism and the host immune system. We describe how an understanding of these processes may guide optimal diagnostic and therapeutic strategies to treat these disorders. Finally, we highlight current gaps in our understanding of disease pathophysiology and call for increased interrogation of these often-neglected disorders of the nervous system.

Peripheral Taenia infection increases immunoglobulins in the central nervous system.

Human cysticercosis is a disease caused by larvae of the cestode Taenia solium. It is an important common cause of adult-onset seizures world-wide where it exacts a debilitating toll on the health and well-being of affected communities. It is commonly assumed that the major symptoms associated with cysticercosis are a result of the direct presence of larvae in the brain. As a result, the possible effects of peripherally located larvae on the central nervous system are not well understood. To address this question, we utilised the Taenia crassiceps intra-peritoneal murine model of cysticercosis, where larvae are restricted to the peritoneal cavity. In this model, previous research has observed behavioural changes in rodents but not the development of seizures. Here we used ELISAs, immunoblotting and the Evans Blue test for blood-brain barrier permeability to explore the central effects of peripheral infection of mice with T. crassiceps. We identified high levels of parasite-targeting immunoglobulins in the sera of T. crassiceps-infected mice. We show that the T. crassciceps larvae themselves also contain and release host immunoglobulins over time. Additionally, we describe, for the first known time, significantly increased levels of IgG within the hippocampi of infected mice, which are accompanied by changes in blood-brain barrier permeability. However, these T. crassiceps-induced changes were not accompanied by alterations to the levels of proinflammatory, pro-seizure cytokines in the hippocampus. These findings contribute to the understanding of systemic and neuroimmune responses in the T. crassiceps model of cysticercosis, with implications for the pathogenesis of human cysticercosis.

Taenia larvae possess distinct acetylcholinesterase profiles with implications for host cholinergic signalling.

Larvae of the cestodes Taenia solium and Taenia crassiceps infect the central nervous system of humans. Taenia solium larvae in the brain cause neurocysticercosis, the leading cause of adult-acquired epilepsy worldwide. Relatively little is understood about how cestode-derived products modulate host neural and immune signalling. Acetylcholinesterases, a class of enzyme that breaks down acetylcholine, are produced by a host of parasitic worms to aid their survival in the host. Acetylcholine is an important signalling molecule in both the human nervous and immune systems, with powerful modulatory effects on the excitability of cortical networks. Therefore, it is important to establish whether cestode derived acetylcholinesterases may alter host neuronal cholinergic signalling. Here we make use of multiple techniques to profile acetylcholinesterase activity in different extracts of both Taenia crassiceps and Taenia solium larvae. We find that the larvae of both species contain substantial acetylcholinesterase activity. However, acetylcholinesterase activity is lower in Taenia solium as compared to Taenia crassiceps larvae. Further, whilst we observed acetylcholinesterase activity in all fractions of Taenia crassiceps larvae, including on the membrane surface and in the excreted/secreted extracts, we could not identify acetylcholinesterases on the membrane surface or in the excreted/secreted extracts of Taenia solium larvae. Bioinformatic analysis revealed conservation of the functional protein domains in the Taenia solium acetylcholinesterases, when compared to the homologous human sequence. Finally, using whole-cell patch clamp recordings in rat hippocampal brain slice cultures, we demonstrate that Taenia larval derived acetylcholinesterases can break down acetylcholine at a concentration which induces changes in neuronal signalling. Together, these findings highlight the possibility that Taenia larval acetylcholinesterases can interfere with cholinergic signalling in the host, potentially contributing to pathogenesis in neurocysticercosis.