Progress in Cell Grafting Therapy for Temporal Lobe Epilepsy

Ashok K. Shetty 0 1 0 A. K. Shetty Department of Surgery (Neurosurgery) and Research Service, Duke University and Durham VA Medical Centers , Durham, NC 27710, USA 1 A. K. Shetty Research Service, Central Texas Veterans Health Care System , Temple, TX 76502, USA 2 ) Institute for Regenerative Medicine, Texas A&M Health Science Center at Scott & White, Department of Molecular and Cellular Medicine , Temple, TX 76502, USA Temporal lobe epilepsy (TLE), exemplified by complex partial seizures, is recognized in ~30% of epileptic patients. Seizures in TLE are associated with cognitive dysfunction and are resistant to antiepileptic drug therapy in ~35% of patients. Although surgical resection of the hippocampus bestows improved seizure regulation in most cases of intractable TLE, this choice can cause lasting cognitive deficiency and reliance on antiepileptic drugs. Thus, alternative therapies that are proficient in both containing the spontaneous recurrent seizures and reversing the cognitive dysfunction are needed. The cell transplantation approach is promising in serving as an adept alternate therapy for TLE, because this strategy has shown the capability to curtail epileptogenesis when used soon after an initial precipitating brain injury, and to restrain spontaneous recurrent seizures and improve cognitive function when utilized after the occurrence of TLE. Nonetheless, this treatment needs further advancement and rigorous evaluation in animal prototypes of chronic TLE before the conceivable clinical use. It is especially vital to gauge the efficacy of distinct donor cell types, such as the hippocampal precursor cells, -aminobutyric acid-ergic progenitors, and neural stem cells derived from diverse human sources (including the embryonic stem cells and induced pluripotent stem cells) for longstanding seizure suppression using continuous electroencephalographic recordings for prolonged periods. Additionally, the identification of the mechanisms underlying the graft-mediated seizure suppression and improved cognitive function, and the development of apt grafting strategies that enhance the anti-seizure and procognitive effects of grafts will be necessary. The goal of this review is to evaluate the progress made hitherto in this area and to discuss the prospect for cell-based therapy for TLE. - Epilepsy affects more than 50 million people worldwide and temporal lobe epilepsy (TLE) is the leading and the most difficult to treat type of epilepsy. Although the etiology of TLE is unknown in most cases, it is typically seen after an initial precipitating injury (IPI), such as status epilepticus (SE), traumatic brain injury, tumors, meningitis, and encephalitis [13]. TLE is seen in more than 30% of epilepsy patients and is typified by multiple hippocampal abnormalities [4, 5]. These include variable loss of principal excitatory neurons in different subfields (also referred to as hippocampal sclerosis), a substantial reduction in the numbers of diverse subclasses of inhibitory -aminobutyric acid positive (GABA-ergic) interneurons, an aberrant synaptic reorganization in the dentate gyrus, altered expression of neurotransmitter receptors and ion channels, hippocampal hyperexcitability due to an increase in the overall excitatory tone vis--vis the inhibitory function, spontaneous complex partial seizures (referred to as spontaneous recurrent seizures [SRS] in animal models of TLE) originating mostly from the hippocampus, and impairments in hippocampal-dependent cognitive function and mood [616]. Although a lifelong intake of antiepileptic drugs (AEDs) is effective for restraining seizures in most patients, a sizeable fraction (>35%) of patients develop intractable TLE [17]. This is typified by sustained occurrences of SRS, despite the intake of AEDs, which submits these patients to the risk of irrepressible seizure activity. Furthermore, long-term AED therapy has side effects, and most TLE patients have memory and mood dysfunction that are not alleviated with AEDs [5, 13, 18, 19]. The treatment choices that are alternative to the intake of AEDs for TLE are inadequate. The ketogenic diet, effective for diminishing seizures in children with refractory epilepsy, has shown limited capability for remedying adult patients and this diet is challenging to persevere for protracted periods [20, 21]. Interventional treatment strategies comprise the surgical resection of the hippocampus and vagus nerve stimulation (VNS). Although the resection surgery intended to eliminate the seizure-generating sector is beneficial for restraining seizures in nearly two thirds of patients with intractable epilepsy, only a subgroup of patients with drug-resistant epilepsy is eligible for surgery, because the seizure-generating zone is not well-delineated and the surgical resection of the hippocampus often leads to significant cognitive impairments, loss of viable tissue, and the possibility of continuing dependence on AEDs [22]. On the other hand, VNS therapy decreases seizure frequency by ~50% in only one third of epilepsy patients [23]. Therefore, novel therapies that are efficacious for both preventing and diminishing SRS, and reversing memory and mood dysfunction in TLE are needed. In this context, cell transplantation approach has promise in serving as an adept alternate therapy for TLE. This is because this strategy has shown the capability to curb epileptogenesis (the succession that modifies a normal brain region into an epileptic precinct) when employed soon after an IPI, and to contain SRS when utilized after the occurrence of TLE in pre-clinical studies [2430]. Because the seizuregenerating zone and the associated cell loss are mainly localized to the hippocampus in most cases, TLE appears to be good candidate to treat it with the cell transplantation approach. The goal of this review is to evaluate the progress made hitherto in this area and to discuss the perspective for cellbased therapy for TLE. The first part of this review discusses the prospects for preventing or minimizing SRS through intracerebral grafting of distinct donor cell types (e. g., hippocampal precursor cells, GABA-ergic progenitors, and neural stem cells [NSCs] from diverse sources) at early time points after an IPI in the hippocampus. The next part of this review confers the efficacy of diverse cell grafts for restraining SRS and easing cognitive dysfunction when used after the occurrence of chronic TLE. Additionally, critical issues that need to be resolved before initiating the clinical use of cell grafting therapy for TLE are discussed. Cell Therapy for Restraining Epileptogenesis Shortly after an Initial Precipitating Injury The ability of the adult hippocampus for self-repair after injury is limited, despite the fact that multipotent and selfrenewing NSCs persist in this region and neurogenesis in the dentate gyrus of the hippocampal formation continues all through life [27, 31, 32]. As a consequence, spontaneous repla (...truncated)