Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery.

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

Fingolimod attenuates gait deficits in mice subjected to experimental autoimmune encephalomyelitis.

Fingolimod, used to treat relapsing-remitting multiple sclerosis (RRMS), reduces motor deficits in mice with established experimental autoimmune encephalomyelitis (EAE). To better characterize the therapeutic effects of fingolimod, kinematic gait analysis was employed to precisely measure movements of a hindleg while EAE mice walked on a treadmill. Relative to the vehicle group, oral dosing with fingolimod, beginning after disease onset (1 mg/kg/day), increased hip heights and knee joint movements, and reduced spinal cord demyelination. These findings suggest that fingolimod preserves gait in RRMS patients by protecting motor circuits in the spinal cord.

A prospective pilot study of cognitive impairment and mood in adults with first seizure, new-onset epilepsy, and newly diagnosed epilepsy at time of initial seizure presentation.

INTRODUCTION: This is an observational prospective cohort study of cognition and mood in individuals presenting to a tertiary neurology clinic with first unprovoked seizure (FS), new-onset epilepsy (NOE), and newly diagnosed epilepsy (NDE). Our aim was to understand the cognitive profile of these three diagnostic groups at the time of first presentation. Follow-up was obtained to evaluate any association between cognition at presentation and subsequent clinical course. METHODS: Forty-three participants (age: 18-60 years) were recruited with FS (n = 17), NOE (n = 16), and NDE (n = 10). Clinical details, neuropsychological testing, and screening for mood disorders were obtained at the time of presentation to clinic. Seizure recurrence was evaluated at clinic follow-up at least 6-12 months following the initial presentation. RESULTS: In all groups, general intelligence (intelligence quotient [IQ]) was consistent with population norms, but more than half of participants (55.8%) were impaired in at least one cognitive domain. The most commonly impaired domain in all diagnostic groups was visuospatial and visuoconstruction suggesting that it may be a sensitive marker of early cognitive impairment. Those with epilepsy (NOE and NDE) at initial presentation were more likely to be impaired than those with FS, particularly on tests of attention, working memory, and processing speed. Seven participants with FS converted to NOE (FSNOE) at follow-up. They were more likely to be impaired on tests of memory than those with FS who did not convert to NOE. On mood screening, 21% of participants scored moderate or severe for depressive symptoms, and 25.6% of participants scored moderate or severe for anxiety symptoms. DISCUSSION: Cognitive impairment and mood changes are common at first seizure presentation and mirror the pattern seen in chronic epilepsy. This cooccurrence of symptomatology at disease onset prior to prolonged antiepilepsy drug exposure suggests a shared underlying disease mechanism and carries important clinical implications for effective diagnosis and management of epilepsy. Furthermore, early cognitive testing may become a clinical biomarker and enable the prediction of an individual's clinical course.