Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid β, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.

Cardiovascular disease remains a major cause of disability and death worldwide. Autonomic imbalance, characterized by suppressed vagal (parasympathetic) activity and increased sympathetic activity, correlates with various pathological conditions, including heart failure, arrhythmia, ischaemia/reperfusion injury and hypertension. Conventionally, pharmacological interventions, such as β-blocker treatment, have primarily targeted suppressing sympathetic over-activation, while vagal modulation has always been neglected. Emerging evidence has documented the improvement of cardiac and vascular function mediated by the vagal nerve. Many investigators have tried to explore the effective ways to enhance vagal tone and normalize the autonomic nervous system. In this review, we attempt to give an overview of these therapeutic strategies, including direct vagal activation (electrical vagal stimulation, ACh administration and ACh receptor activation), pharmacological modulation (adenosine, cholinesterase inhibitors, statins) and exercise training. This overview provides valuable information for combination therapy, contributing to establishment of a comprehensive system on vagal modulation from the aspects of clinical application and lifestyle improvement. In addition, the mechanisms contributing to the benefits of enhancing vagal tone are diverse and have not yet been fully defined. We endeavour to outline the recent findings that advance our knowledge regarding the many favourable effects exerted by vagal activation: anti-inflammatory pathways, modulation of NOS and NO signalling, regulation of redox state, improvement of mitochondrial biogenesis and function, and potential calcium regulation. This review may help to develop novel therapeutic strategies targeting enhancing vagal activity for the treatment of cardiovascular diseases.

After partial nerve injury, the central analgesic effect of systemically administered gabapentin is mediated by both supraspinal and spinal actions. We further evaluate the mechanisms related to the supraspinally mediated analgesic actions of gabapentin involving the descending noradrenergic system. Intracerebroventricularly (i.c.v.) administered gabapentin (100 microg) decreased thermal and mechanical hypersensitivity in a murine chronic pain model that was prepared by partial ligation of the sciatic nerve. These effects were abolished by intrathecal (i.t.) injection of either yohimbine (3 microg) or idazoxan (3 microg), alpha(2)-adrenergic receptor antagonists. Pretreatment with atropine (0.3 mg kg(-1), i.p. or 0.1 microg, i.t.), a muscarinic receptor antagonist, completely suppressed the effect of i.c.v.-injected gabapentin on mechanical hypersensitivity, whereas its effect on thermal hypersensitivity remained unchanged. Similar effects were obtained with pirenzepine (0.1 microg, i.t.), a selective M(1)-muscarinic receptor antagonist, but not with methoctramine (0.1 and 0.3 microg, i.t.), a selective M(2)-muscarinic receptor antagonist. The cholinesterase inhibitor neostigmine (0.3 ng, i.t.) potentiated only the analgesic effect of i.c.v. gabapentin on mechanical hypersensitivity, confirming spinal acetylcholine release downstream of the supraspinal action of gabapentin. Moreover, the effect of i.c.v. gabapentin on mechanical but not thermal hypersensitivity was reduced by i.t. injection of L-NAME (3 microg) or L-NMMA (10 microg), both of which are nitric oxide (NO) synthase inhibitors. Systemically administered naloxone (10 mg kg(-1), i.p.), an opioid receptor antagonist, failed to suppress the analgesic actions of i.c.v. gabapentin, indicating that opioid receptors are not involved in activation of the descending noradrenergic system by gabapentin. Thus, the supraspinally mediated effect of gabapentin on mechanical hypersensitivity involves activation of spinal alpha(2)-adrenergic receptors followed by muscarinic receptors (most likely M(1)) and the NO cascade. In contrast, the effect of supraspinal gabapentin on thermal hypersensitivity is independent of the spinal cholinergic-NO system.