Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid ␤-amyloid peptide (A␤ 1-42 ) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that A␤ 1-42 and a neuronal pentameric cation channel, the ␣7 nicotinic acetylcholine receptor (␣7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either ␣7nAChR or amyloid precursor protein as the starting material, A␤ 1-42 and ␣7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the ␣7nAChR⅐A␤ 1-42 complex can be efficiently suppressed by A␤ 12-28 , implying that this A␤ sequence region contains the binding epitope. Receptor binding experiments show that A␤ 1-42 and ␣7nAChR bind with high affinity, and this interaction can be inhibited by ␣7nAChR ligands. Human neuroblastoma cells overexpressing ␣7nAChR are readily killed by A␤ 1-42 , whereas ␣7nAChR agonists such as nicotine and epibatidine offered protection. Because A␤ 1-42 inhibits ␣7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of ␣7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the ␣7nAChR and A␤ 1-42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.Evidence obtained from familial Alzheimer's disease (AD) 1 patients (1-3) and transgenic animals (4 -7) overexpressing amyloid precursor protein (APP) indicates that A␤ 1-42 is a causal factor of neuritic plaque formation and neurodegeneration in AD. A␤ peptides are known to bind specifically to the scavenger receptors expressed in microglia and macrophages (8, 9) and the ubiquitous receptor for advanced glycation end products (RAGE) (10, 11). A␤ binding to scavenger receptors may induce cell death by generating free radicals (12, 13), whereas binding to RAGE may promote A␤ clearance (10, 11). However, the respective receptor function and distribution pattern for scavenger receptors and RAGE cannot fully explain the A␤ 1-42 -induced pathophysiology observed in AD such as cognitive and memory impairment, in which cholinergic neurons are involved. This suggests that additional physiologically relevant neuronal receptors for A␤ 1-42 may exist.The ␣7 nicotinic acetylcholine receptor (␣7nAChR) is highly expressed in the basal forebrain cholinergic neurons that project to the hippocampus and cortex of normal and AD brains (14, 15), correlating well with brain areas that exhibit neuritic plaques in AD. More importantly, the ␣7nAChR modulates calcium homeostasis and release of the neurotransmitter acetylcholine, two important parameters involved in cognition and memory. We thus investigated the molecular and bioche...

In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.Topiramate (TPM; RWJ-17021-000, McN-4853) was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis. Sulfamate derivatives of fructose were the initial focus of the synthetic effort because they contain unionized groups that might simulate phosphate binding to the enzyme and also facilitate access to the enzyme by enhancing membrane permeability.TPM was prepared as a synthetic intermediate in the project, and it is devoid of hypoglycemic activity. However, the structural resemblance of its 0-sulfamate moiety to the sulfonamide moiety in acetazolamide (and other arenesulfonamide anticonvulsants) prompted an evaluation of possible anticonvulsant effects. TPM was highly active in the traditional maximal electroshock seizure (MES) test in mice and rats and possessed a long duration of action (1-3). Furthermore, there was a wide separation between the effective anticonvulsant doses compared to those causing motor impairment. Development of TPM as an antiepileptic drug (AED) was subsequently pursued on the basis of its potency, duration of action, and high neuroprotective index.

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Abstract:We have recently reported evidence that a very high affinity interaction between the ␤-amyloid peptide A␤ 1-42 and the ␣7 nicotinic acetylcholine receptor (␣7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of A␤ 1-42 to ␣7nAChR and ␣4␤2nAChR were determined using the subtypeselective nicotinic receptor ligands [3 H]methyllycaconitine and [3 H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. A␤ 1-42 bound to the ␣7nAChR with exceptionally high affinity, as indicated by K i values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the ␣7nAChR, the affinity of A␤ 1-42 for the ␣4␤2nAChR was ϳ5,000-fold lower, as indicated by corresponding K i values of 30 and 23 nM. The results of this study support the concept that an exceptionally high affinity interaction between A␤ 1-42 and ␣7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.