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Browsing by Subject "Levetiracetam"

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    Identifying the mechanism of action of the antiepileptic drug levetiracetam in synaptic vesicle release and its implications for epilepsy.
    (2011-07) Meehan, Anna L.
    In the United States alone, over 3 million people have been diagnosed with epilepsy, a dynamic disease characterized by recurring and unpredictable seizures. Antiepileptic drugs (AEDs) and other therapies have helped to combat this widespread phenomenon, yet for one-third of epilepsy patients, there is still no effective treatment. A better understanding of the mechanisms of AEDs has been called for. Levetiracetam (LEV) is one AED on the market that does not work by the typical mechanisms of action of AEDs. LEV binds to the vesicular protein SV2A in neurons in the brain, which is thought to mediate some step in neurotransmitter release. However, the exact mechanism of action of LEV is unknown. Deducing this mechanism would be of substantial benefit for the development of new, similar drugs that also work by such a non-conventional mechanism. The experiments and results I present in this dissertation detail my investigation of the effect of LEV on neurotransmission of rat hippocampal neurons. My methods include fluorescence-staining with FM dyes to label synaptic vesicles and monitor vesicle release as well as electrophysiological techniques to observe synaptic currents. My experimental protocols have allowed me to detect differences in neurotransmitter release in LEV-treated neurons. Furthermore, manipulating exposure conditions required before LEV action have allowed me to deduce that LEV must enter active neurons to reach SV2A. I believe that LEV is dependent on endocytosis for access to vesicles, a completely unique mechanism of action for a small molecule drug.
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    Levetiracetam prevents neurophysiological changes and preserves cognitive function in the HIV-1 TAT transgenic mouse model of HIV-associated neurocognitive disorder
    (2024) Ewens, Ashley
    Worldwide, 39 million people are currently HIV-positive; around half of these individuals also suffer from HIV-associated neurocognitive disorder (HAND). HAND symptoms range from subclinical cognitive impairment to HIV-associated dementia. Once people living with HIV (PLWH) have one form of HAND, they are at much higher risk of developing more severe types, which are correlated with worse prognosis and decreased survival. Currently, there is no treatment available specifically for HAND and its mechanism of manifestation has not been fully elucidated. Combined antiretroviral therapy (cART), the first line treatment for HIV, has greatly extended the lifespan of PLWH. However, cART has not improved the prevalence of HAND. This suggests that HIV can continue to cause damage even at virologically controlled levels. Indeed, the virus lies latent in microglial viral reservoirs and continues to produce HIV-associated proteins, several of which have been implicated in HAND. There is conclusive evidence that trans-activator of transcription (TAT) persists in the central nervous system despite cART and contributes to the development of HAND. TAT has a wide range of neurotoxic effects, the most damaging of which include magnifying inflammation, impairing the endocannabinoid system, over-activating NMDA receptors, and upregulating inhibitory signaling. In addition, TAT aids the HIV virus in attracting and entering uninfected immune cells, supporting its continued replication. Therefore, a treatment specifically against TAT’s neurotoxicity deserves more investigation. Overall, the modifications to the immune system, endocannabinoid system, NMDA receptors, and inhibitory signaling create an environment conducive to excitatory dysfunction. TAT has also been shown to directly manipulate glutamate signaling and cycling. As a result, TAT has been implicated in causing epileptic activity, although there is limited research. This is supported by the evidence that PLWH have seizures five times more than the general population. Additionally, epileptic activity has been demonstrated to be pathogenic in Alzheimer’s disease (AD), which bears many similarities to HAND pathology. Excitingly, not only could this activity be reversed in AD-model mice, but cognition was also preserved using an anti-epileptic drug, levetiracetam (LEV). Since PLWH are at risk for developing seizures that may worsen cognition, LEV could be used as a protective strategy against seizures and cognitive decline. Here, I show for the first time that LEV prevented synaptic and cognitive impairments that develop in a TAT-expressing mouse model. Inducible TAT (iTAT) transgenic male mice had an increased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) in hippocampal slice recordings. Furthermore, iTAT mice had impaired long-term potentiation (LTP), a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV through osmotic minipumps prevented both impairments. Additionally, kainic acid induced a higher maximum behavioral seizure score, longer seizure duration, and a shorter latency to first seizure, consistent with a lower seizure threshold in iTAT mice. Acute LEV administration reduced seizures in control and iTAT mice. Lastly, iTAT mice showed cognitive impairments in the Barnes maze that were prevented by chronic LEV administration. Thus, a TAT-induced increase in glutamatergic synaptic activity drives functional deficits in this model of HAND. LEV not only prevented aberrant synaptic activity in iTAT mice, but also restored cognitive function. LEV provides a pharmacological approach to prevent neurodegenerative processes and is a promising strategy to afford neuroprotection in HAND. This study supports further investigation of the use of LEV for clinical neuroprotection in HAND patients.