eprintid: 10042152 rev_number: 54 eprint_status: archive userid: 608 dir: disk0/10/04/21/52 datestamp: 2018-03-16 13:04:12 lastmod: 2021-03-02 23:10:34 status_changed: 2018-03-16 13:04:12 type: thesis metadata_visibility: show creators_name: Khan, Archie Arunima title: Investigating the mechanisms of action of phytocannabinoids and a novel cognitive enhancer to target the comorbidity of temporal lobe epilepsy ispublished: unpub divisions: UCL divisions: A01 divisions: B02 divisions: C08 abstract: Temporal lobe epilepsy (TLE) is the most common type of epilepsy and exists with memory loss as a comorbidity. The conventional therapy available to treat these disorders achieves only modest therapeutic efficacy at best. This study investigates two potential treatments: phytocannabinoids to alleviate seizures, and a novel cognitive enhancer to restore/halt memory deficits. The anti-convulsant properties of cannabidiol (CBD) were first examined with regards to the neuropathology of two major types of hippocampal interneurons expressing parvalbumin (PV) and cholecystokinin (CCK) which are thought to dysfunction during epilepsy. Immunohistochemistry experiments using an in vivo kainic-acid induced epileptic rat model, revealed that PV- and CCK-immunopositive interneurons were significantly affected during epilepsy. This effect was greatly reduced following CBD treatment, suggesting that CBD exerts a neuroprotective function. The effects of CBD on the intrinsic membrane properties of these interneurons, together with hippocampal pyramidal cells, were further investigated in acute brain slices of rat seizure models of TLE (in vivo kainic acid-induced and in vitro Mg2+ free-induced). Whole-cell recordings revealed that bath application of CBD (10 µM) normalised the firing frequency of epileptic adapting pyramidal cells to healthy control levels. A similar effect was seen in hippocampal CCK-immunopositive Schaffer collateral associated (SCA) interneurons. In contrast, CBD resulted in an increased firing of PV-immunopositive interneurons, thus increasing their excitability and restoring the impaired membrane properties of the cells apparent in the epileptic models. The effects of cannabidivarin (CBDV), a similar cannabinoid compound, on the intrinsic membrane properties of these cell types were also evaluated. Additionally, CBDV affected excitatory postsynaptic currents by reducing excitation. In an attempt to address the memory impairment aspect associated with TLE, I investigated the neuronal effects of a5AM21, a novel potential memory enhancer. Electrophysiological experiments revealed that a5AM21 preferentially acts on 5-containing gamma (γ)-aminobutyric acid (GABA) type A (GABAA) receptors, reducing their inhibitory effects. Furthermore, data obtained using behavioural experiment paradigm, the eight-arm radial maze, suggest a significant improvement in short- and long-term memory retrieval in rats treated with a5AM21. In conclusion, the results reveal the potential mechanisms of action of two therapies to alleviate seizures and memory impairment, and the future goals would be to combine CBD/CBDV and a5AM21 as a promising novel targeted therapy for TLE. date: 2018-02-28 date_type: published oa_status: green full_text_type: other thesis_class: doctoral_open thesis_award: Ph.D language: eng thesis_view: UCL_Thesis primo: open primo_central: open_green verified: verified_manual elements_id: 1529198 lyricists_name: Khan, Archie lyricists_id: AAKHA54 actors_name: Khan, Archie actors_id: AAKHA54 actors_role: owner full_text_status: public pages: 242 event_title: UCL institution: UCL (University College London) department: UCL School of Pharmacy thesis_type: Doctoral citation: Khan, Archie Arunima; (2018) Investigating the mechanisms of action of phytocannabinoids and a novel cognitive enhancer to target the comorbidity of temporal lobe epilepsy. Doctoral thesis (Ph.D), UCL (University College London). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10042152/1/Archie%20Khan_Thesis_edited%20version.pdf