Behavioral Effects of Gangliosides: Anatomical Considerations

Gangliosides are endogenous sialic acid containing glycospingolipids which are highly concentrated in the central nervous system. Although they were first characterized over 40 years ago, the function(s) played by this unique class of lipids remain largely unknown. Gangliosides have been suggested to play a prominent role in both normal and abnormal developmental processes. In addition, several lines of convergent evidence have indicated that gangliosides exert pronounced trophic effects following damage to peripheral and central nerves. Gangliosides have been shown to (1) enhance cell survival and outgrowth in cultured and developing neurons; (2) promote the regeneration of damaged peripheral and central nerves, and (3) facilitate behavioral recovery by altering the pattern, extent and persistence of the biochemical, morphological and behavioral changes induced by neural trauma. Little is known, however, concerning the neurobiological mechanisms which subserve the. behavioral protection afforded by ganglioside treatment. This review focuses on the evidence suggesting that gangliosides mediate functional recovery by minimizing primary or secondary cell loss or promoting the regeneration or sprouting of damaged central nerves subsequent to injury. An understanding of the mechanisms, by which gangliosides produce their effects may lead to the development of more efficacious and rational primary or adjunct pharmacological treatments for central nervous system disorders

Encapsulated Cell Therapy for The Treatment of Epilepsy

Contemporary antiepileptic drugs are ineffective in approximately 30% of the patients. These patients continue to experience seizures and, in many cases, seizures increase in frequency and are associated with significant cognitive decline and psychiatric disorders. The delivery of trophic factors such as glial cell-derived neurotrophic factor (GDNF) to the CNS has tremendous potential for treating a range of diseases including epilepsy. We have recently tested a clinically-validated, implantable cell encapsulation system (EC) that delivers high levels of GDNF in a selective, long-term and stable manner to the epileptogenic area of pilocarpine treated rats. As such, this therapeutic technology platform combines the potency of de novo in situ synthesis of cell-derived GDNF with the safety of an implantable, biocompatible, and retrievable medical device. The de novo synthetized source of very high levels of GDNF in the brain region of interest proved able to significantly reduce generalized seizures frequency, improved cognitive performance and normalized anatomical alterations associated with chronic epilepsy

Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson'sDisease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19cells to deliver of GDNF to the brain. In vivostudies demonstrated sustained delivery of GDNF to the rat striatumover 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigraldopaminergic neurons were preserved in neuroprotection studies and dopaminergicfibers were restored inneurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen ofG\u20acottingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significantupregulation of tyrosine hydroxylase immunohistochemistry. These results are thefirst to provide clear evidencethat implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts ofGDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson'sdiseas

Effect of Fetal Striatal and Astrocyte Transplants into Unilateral Excitotoxin-Lesioned Striatum

Studies have suggested that neurotrophic mechanisms may underlie transplant-induced functional recovery. Astrocytes have been reported to be a source of neurotrophic factors. The present study examined the possible role of cultured astrocytes in promoting recovery of apomorphine-induced rotation behavior in rats with unilateral kainic acid (KA) lesions of the striatum. Five weeks after the lesions, one group of rats received fetal striatal tissue (E17) transplants, another group received transplants of cultured astrocyte suspension, and the remaining rats received sham transplants and served as controls. Apomorphine-induced rotation behavior was tested 4 weeks after the KA lesions, and 5 and 10 weeks following the transplantation. The KA-induced rotation behavior was reduced by the striatal transplants but not by the cultured astrocyte transplants 5 and 10 weeks following the transplantation. Histochemicai analysis indicated that the striatal transplants had survived and grown and contained neurons and glia with similar morphology to those in the host brain. Immunocytochemical analysis of the astrocyte transplant sites revealed heavy glial fibrillary acidic protein and OX-42 staining in the transplant areas, suggesting that the transplanted astrocytes may have survived in the host brain. Although fetal striatal transplants can ameliorate apomorphine-induced rotation behavior, transplants of astrocytes alone may not be sufficient to reverse the functional deficits produced by KA lesions

Encapsulated cell therapy in a rat model of epilepsy: long-term, stable, and efficacious targeting of the hippocampus with GDNF

Contemporary antiepileptic drugs are ineffective in approximately 30% of the patients. These patients continue to experience seizures and, in many cases, their seizures increase in frequency and become associated with significant cognitive decline and psychiatric disorders (Klein et al., 2018). The delivery of trophic factors such as glial cell-derived neurotrophic factor (GDNF) to the CNS has tremendous potential for treating a range of diseases including epilepsy. We have developed a clinically-validated, implantable cell encapsulation system (EC) that delivers high levels of GDNF in a selective, long-term and stable manner to the epileptogenic area. As such, this therapeutic technology platform combines the potency of de novo in situ synthesis of cell-derived GDNF with the safety of an implantable, biocompatible, and retrievable medical device. This approach is based on enclosing ARPE-19 cells genetically modified to secrete GDNF in an immunoprotective membrane before transplantation (Fjord-Larsen et al., 2012; Emerich et al., 2014). Initial studies confirmed the long-term (24 weeks) and targeted delivery of GDNF to the rat hippocampus. In subsequent studies, pilocarpine-treated rats, while experiencing spontaneous recurring seizures, received bilateral implants of EC-GDNF devices into the ventral hippocampus. While the number of seizures continued unimpeded in control rats, treatment with EC-GDNF devices reduced seizures by approximately 80% within 2 weeks and by more than 90% within 3 months. These effects persisted even after device retrieval, suggesting potential disease-modifying benefits. Because neuropsychological impairment is a critical co-morbidity of chronic epilepsy we investigated the effects of EC-GDNF on the nature and time course of anxiety-like behaviours and cognitive impairments occurring in pilocarpine treated rats. Importantly, treatment with EC-GDNF maintained normal learning and memory capabilities and normal anxiety-like behaviour. These neurological benefits were associated with the normalization of several anatomical alterations accompanying chronic epilepsy, including preventing hippocampal atrophy, cell degeneration, loss of parvalbumin positive interneurons, and abnormal neurogenesis (Paolone et al., under revision). These studies consistently demonstrated that encapsulated GDNF-secreting cells produce long-term and robust elevations in hippocampal GDNF that are well-tolerated, efficacious and perhaps disease modifying across a spectrum of epilepsy-relevant neurological measures. This approach represents a potentially novel and effective treatment for epilepsy

Cellular delivery of NGF does not alter the expression of β-amyloid immunoreactivity in young or aged nonhuman primates

The present study determined whether grafts of nerve growth factor- producing fibroblasts alter the expression of β-amyloid in young or aged nonhuman primates. Aged monkeys serve as an animal model which normally exhibits β-amyloid-laden plaques. Three young adult (7-12 years of age) and three aged (24-29 years of age) rhesus monkeys received intraventricular implants of polymer-encapsulated cells that were genetically modified to secrete human recombinant nerve growth factor (NGF). Three young adult and three aged rhesus monkeys received identical treatment except that the grafted cells were not genetically modified and thus differed only by a single gene construct. Five additional aged rhesus monkeys were ungrafted and also served as controls. Three to four weeks posttransplantation, young monkeys did not display β-amyloid-immunoreactive profiles within any CNS structure regardless of treatment. Qualitative observations revealed that aged monkeys displayed numerous β-amyloid plaque-like structures within the amygdala and hippocampus as well as limbic and neocortices. The amount of β- amyloid immunoreactivity (β-amyloid load) was quantified bilaterally within the temporal neocortex of these animals. The β-amyloid load within the temporal neocortex of aged monkeys was highly variable but did not differ across treatment groups. These data indicate that chronic short-term administration of NGF does not affect the expression of β-amyloid in the young or the aged primate brain