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

Advances in cell-laden hydrogels for delivering therapeutics

Almost six decades ago, a visionary scientist reported a new method for encapsulating aqueous solutions of protein within semipermeable polymer membranes [1]. This approach was successfully tested in the 1970s and 1980s by immobilizing xenograft islet cells to control glucose metabolism in small animal models [2,3]. Since then, the concept of cell-laden hydrogels has evolved and progressed but still those pioneering works are perfect examples of the theoretical advantages that this approach may offer in terms of long-term delivery and immune protection [4]. In its most basic form, cell-laden hydrogels or bioartificial organs consist of a polymeric or synthetic membrane structure that entraps a wide range of cells releasing bioactive drugs or proteins [5,6]. The three-dimensional (3D) constructs, typically either shaped as a microcapsule or a hollow-fiber, will regulate with different efficiency the permeability and mechanical stability of the cell-based medicine [7]. The semipermeable membrane is responsible for preventing high molecular weight molecules, antibodies and other immunologic components from entering within the construct but also controls the inward/outward diffusion of critical agents for cell survival and therapeutic efficacy including nutrients, oxygen, waste agents and therapeutic protein products (Figure 1). Even though the journey from theory to practice has been demanding and challenging, recent progress in the field is creating new avenues of hope to use this approach in several unmet clinical needs ranging from diabetes to ophthalmological disorders or rare diseases

Glucocorticoid receptors modulate dendritic spine plasticity and microglia activity in an animal model of Alzheimer's disease

Abstract Chronic exposure to high circulating levels of glucocorticoids (GCs) may be a key risk factor for Alzheimer's Disease (AD) development and progression. In addition, hyper-activation of glucocorticoid receptors (GRs) induces brain alterations comparable to those produced by AD. In transgenic mouse models of AD, GCs increase the production of the most important and typical hallmarks of this dementia such as: Aβ40, Aβ42 and tau protein (both the total tau and its hyperphosphorylated isoforms). Moreover, GCs in brain are pivotal regulators of dendritic spine turnover and microglia activity, two phenomena strongly altered in AD. Although it is well-established that GCs primes the neuroinflammatory response in the brain to some stimuli, it is unknown whether or how GRs modulates dendritic spine plasticity and microglia activity in AD. In this study, we evaluated, using combined Golgi Cox and immunofluorescence techniques, the role of GR agonists and antagonists on dendritic spine plasticity and microglia activation in hippocampus of 3xTg-AD mice. We found that dexamethasone, an agonist of GRs, was able to significantly reduce dendritic spine density and induced proliferation and activation of microglia in CA1 region of hippocampus of 3xTg-AD mice at 6 and 10 months of age. On the contrary, the treatment with mifepristone, an antagonist of GRs, strongly enhanced dendritic spine density, decreased microglia density and improved the behavioural performance of 3xTg-AD mice. Additionally, primary microglial cells in vitro were directly activated by dexamethasone. Together, these data demonstrate that stress exacerbates AD and promotes a rapid progression of the pathology acting on both neurons and glial cells, supporting an important pro-inflammatory role of GC within CNS in AD. Consequently, these results further strengthen the need to test clinical interventions that correct GCs dysregulation as promising therapeutic strategy to delay the onset and slow down the progression of AD

Cell-laden alginate hydrogels for the treatment of diabetes

Diabetes mellitus is an ever-increasing medical condition that currently suffers 1 of 11 adults who may have lifelong commitment with insulin injections. Cell-laden hydrogels releasing insulin may provide the ultimate means of correcting diabetes. Here, we provide insights of this cell-based approach including latest preclinical and clinical progress both from academia and industry

From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson’s Disease

Prime Archives in Neuroscience is a compilation of recent advances in multidisciplinary topics relating to the nervous system

From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson's Disease

Parkinson's disease (PD) is a complex, multisystem, progressive, degenerative disorder characterized by severe, debilitating motor dysfunction, cognitive impairments, and mood disorders. Although preclinical research has traditionally focused on the motor deficits resulting from the loss of nigrostriatal dopaminergic neurons, up to two thirds of PD patients present separate and distinct behavioral changes. Loss of basal forebrain cholinergic neurons occurs as early as the loss of dopaminergic cells and contributes to the cognitive decline in PD. In addition, attentional deficits can limit posture control and movement efficacy caused by dopaminergic cell loss. Complicating the picture further is intracellular \u3b1-synuclein accumulation beginning in the enteric nervous system and diffusing to the substantia nigra through the dorsal motor neurons of the vagus nerve. It seems that \u3b1-synuclein's role is that of mediating dopamine synthesis, storage, and release, and its function has not been completely understood. Treating a complex, multistage network disorder, such as PD, likely requires a multipronged approach. Here, we describe a few approaches that could be used alone or perhaps in combination to achieve a greater mosaic of behavioral benefit. These include (1) using encapsulated, genetically modified cells as delivery vehicles for administering neuroprotective trophic factors, such as GDNF, in a direct and sustained means to the brain; (2) immunotherapeutic interventions, such as vaccination or the use of monoclonal antibodies against aggregated, pathological \u3b1-synuclein; (3) the continuous infusion of levodopa-carbidopa through an intestinal gel pad to attenuate the loss of dopaminergic function and manage the motor and non-motor complications in PD patients; and (4) specific rehabilitation treatment programs for drug-refractory motor complications. Introductio

Deficits in attentional control: Cholinergic mechanisms and circuitry-based treatment approaches.

The cognitive control of attention involves maintaining task rules in working memory (or “online”), monitoring reward and error rates, filtering distractors, and suppressing prepotent and competitive responses. Weak attentional control increases distractibility and causes attentional lapses, impulsivity and attentional fatigue. Levels of tonic cholinergic activity (changes over tens of seconds or minutes) modulate cortical circuitry as a function of the demands on cognitive control. Increased cholinergic modulation enhances the representation of cues, by augmenting cue-evoked activity in thalamic glutamatergic afferents, thereby increasing the rate of detection. Such cholinergic modulation is mediated primarily via α4β2* nicotinic acetylcholine receptors. Animal experiments and clinical trials in adult patients with ADHD indicate that attentional symptoms and disorders may benefit from drugs that stimulate this receptor. Tonic cholinergic modulation of cue-evoked glutamatergic transients in prefrontal regions is an essential component of the brain’s executive circuitry. This circuitry model guides the development of treatments of deficits in attentional control

Dissociation in the modulatory effects of environmental novelty on the locomotor, analgesic, and eating response to acute and repeated morphine in the rat

RATIONALE: We have previously shown that environmental novelty can potentiate the activating effects of morphine and the development of sensitization to this effect. OBJECTIVES. Our main goal was to determine whether environmental novelty can also modulate the prophagic (time spent eating and food intake; experiment 1) and/or the analgesic (tail-flick test; experiments 2 and 3) effect of morphine, as well as the development of tolerance or sensitization to these effects. METHODS: In experiment 1, two groups of rats were administered seven intraperitoneal (i.p.) injections of either saline or morphine (4.0 mg/kg) either in their home cages (home groups) or in a distinct environment (novelty groups). After 7 days of withdrawal, both groups underwent a morphine challenge (4.0 mg/kg, i.p.). In experiment 2, home and novelty rats were administered four doses of morphine (0.0, 2.0, 4.0, and 8.0 mg/kg, i.p.) following a counterbalanced order. In experiment 3, home and novelty rats were administered eight intraperitoneal (i.p.) injections of either saline or morphine (8.0 mg/kg) and then given a morphine challenge (4.0 mg/kg). RESULTS: Environmental novelty enhanced the locomotor activating effect of morphine and the expression of sensitization to this effect (even after a period of withdrawal). Environmental novelty had relatively little effect on morphine-induced eating, and no effect on morphine-induced analgesia. CONCLUSIONS: Environmental context can have very different consequences on distinct drug effects as well as on distinct neurobehavioral adaptations to the same drug treatment (e.g., psychomotor sensitization versus analgesic tolerance)

Ecocebo: how the interaction between environment and drug effects may improve pharmacotherapy outcomes

: This narrative review describes the research on the effects of the association between environmental context and medications, suggesting the benefit of specific design interventions in adjunction to pharmacotherapy. The literature on Evidence-Based Design (EBD) studies and Neuro-Architecture show how contact with light, nature, and specific physical features of urban and interior architecture may enhance the effects of analgesic, anxiolytics, and antidepressant drugs. This interaction mirrors those already known between psychedelics, drugs of abuse, and setting. Considering that the physical feature of space is a component of the complex placebo configuration, the aim is to highlight those elements of built or natural space that may help to improve drug response in terms of efficacy, tolerability, safety, and compliance. Ecocebo, the integration of design approaches such as EBD and Neuro-Architecture may thus contribute to a more efficient, cost-sensitive, and sustainable pharmacotherapy