PHARMACOLOGICAL EVALUATION OF EXTRASYNAPTIC GABAA RECEPTORS AND THEIR ROLE EARLY IN STROKE

γ-Aminobutyric Acid type A receptors (GABAARs) represent a diverse class of pentameric ligand-gated ion channels. Sixteen subunits of GABAARs (α1–6, β1–3, γ1–3, δ, ε, θ and π) have been identified so far, giving rise to structural heterogeneity of GABAARs which vary in their pharmacological properties. GABAARs that contain the α4 and δ subunits are located extrasynaptically, mediating tonic currents elicited by low concentrations of GABA. These α4βδ receptors are modulated by neurosteroids and certain anaesthetics, identifying them as important drug targets in research. These receptors are also implicated in numerous neurodegenerative and psychiatric disorders including epilepsy, sleep disorders, depression and stroke. This thesis discusses the pharmacological properties of α4βδ receptors expressed in Xenopus oocytes and how modulation of these receptors using a δ-preferred agonist, THIP, affects recovery in a mouse model of stroke. We also sought to identify an additional binding site for THIP that confers the distinct activation level of THIP at the extrasynaptic δ-containing receptors and the synaptic γ-containing receptors. Despite the growing interest in α4βδ receptors in the past decade, pharmacological studies on these receptors have often yielded variable results, possibly due to the expression of receptors in different subunit compositions (stoichiometries) or arrangements. In this study, we created a matrix of different mRNA injection ratios of α4, β2 and δ subunits expressed in Xenopus oocytes and measured the sensitivity to GABA and DS2 activation of the resulting receptor populations using two-electrode voltage clamp. We identified two distinct populations of receptors, the first with a GABA EC50 value of ~100 nM, a low Hill slope of ~0.3 and substantial direct activation by DS2. The second population had a GABA EC50 value of ~1 μM, a steeper Hill slope of 1 and little direct activation, but substantial potentiation, by DS2. The two distinct receptor populations differ in their stoichiometry, which confers differences in their pharmacology and thus underlies contradictory results between different laboratories. Tonic currents elicited by the extrasynaptic receptors are involved in stroke. The development of selective compounds for stroke treatments is very promising as they target subtypes of GABAARs implicated in stroke and minimize the side effects. The administration of L655,708, a negative allosteric modulator of α5-containing receptors, 3-14 days following stroke to decrease tonic currents resulted in improved recovery in a mouse model of phototrombotic stroke. When L655,708 was given immediatel

Penyuluhan dan Workshop Obat Nyamuk Sintetis dan Alami Sebagai Tindakan Pencegahan DBD

Selama bulan Januari-Februari 2016, Jakarta Timur menduduki peringkat kedua dalam jumlah penderita DBD. Hal ini diperkirakan karena kurangnya partisipasi masyarakat dalam pemberantasan sarang nyamuk dan menjaga sanitasi. Hingga saat ini, masyarakat umum menggunakan obat pengusir nyamuk untuk menghindari gigitan nyamuk. Namun penggunaan pengusir nyamuk sintetis dengan cara yang salah dan dalam jangka waktu lama dapat berdampak buruk terhadap kesehatan. Kegiatan Pengabdian Masyarakat ini bertujuan untuk meningkatkan pengetahuan masyarakat mengenai bahaya penggunaan obat pengusir nyamuk sintetis dan pemberian solusi melalui bahan alamiah berkhasiat mengusir nyamuk. Kegiatan ini dilakukan di wilayah RW 11, Pulomas Barat, DKI Jakarta dengan melibatkan kelompok ibu PKK dan Jumantik (Jumat Bebas Jentik) dan dihadiri oleh 37 orang partisipan. Hasil evaluasi menunjukkan bahwa pengetahuan para partisipan mengenai bahaya obat nyamuk sintetis beserta cara pembuatan obat nyamuk alami meningkat setelah penyuluhan. Data mengenai tingkat penggunaan obat pengusir nyamuk di daerah warga juga berhasil diperoleh. Para partisipan dilatih membuat lotion pengusir nyamuk dari bahan alami diakhir kegiatan. Kegiatan ini diharapkan dapat meningkatkan kesadaran masyarakat untuk berpartisipasi aktif dalam menurunkan angka kejadian penyakit DBD dengan memanfaatkan bahan-bahan alami yang terjangkau dan mudah diperoleh