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Alzheimer's disease (AD), the leading disorder of memory impairment in our aging population, is increasing at an alarming rate. AD is currently identified by three 'gold standard criteria': (i) dementia in life, (ii) amyloid plaques at autopsy, and (iii) neurofibrillary tangles at autopsy. Several autopsy studies have indicated that dementia in life is a consequence of lost synaptic networks in the brain, while many clinical trials targeting neurotoxic amyloid beta (Aβ) have consistently failed to produce therapeutic effects on memory function in AD patients. Restoring cognitive function(s) by activating endogenous repairing/regenerating mechanisms that are synaptogenic and antiapoptotic (preventing neuronal death), however, is emerging as a necessary disease-modifying therapeutic strategy against AD and possibly for other degenerative dementias, such as Parkinson's disease and multi-infarct dementia.

Executive functioning is a high-level cognitive ability, regulating other abilities and behaviors to achieve desired goals. A typical executive task can be defined as the capacity to maintain one's attention on the current task, that is, responding only to the correct but not to distractive stimuli. Impairments of executive functions, or executive dysfunctions, have a growing impact on everyday life and academic achievement and are usually an early feature, and one of the core features, in brain injury and memory and behavioral disorders. Furthermore, emerging evidence indicates that memory therapeutics cannot achieve their clinical benefits in cognition if executive dysfunction is not effectively and simultaneously treated. Improvement of executive functions might be achieved through targeting some signaling pathways in the brain, including the brain-derived neurotrophic factor signaling pathways. These agents may be useful either as stand-alone interventions for patients with executive dysfunction and/or psychiatric and memory disorders or as essential adjuncts to drugs that target the underlying pathology in various brain injury and memory and behavioral disorders.

Despite over a half-century's intensive research worldwide, the currently available antidepressants remain sub-optimal. Therapeutic options for treatment-resistant depression, for instance, are rather limited. Here, we found that rats exhibited a lasting treatment-resistant depressive immobility in response to open space swim test at a high intensity of induction. The induced depressive behavior is associated with a dramatic impairment in spatial learning and memory. Both the depressive immobility and impairment in spatial learning and memory are sensitive to a period of chronic treatment with bryopstatin-1, a relatively selective activator of protein kinase Cε. Bryostatin-1-like analogues therefore might have therapeutic values for the treatment of treatment-resistant depression.

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.

Evidence is accumulating that many memory disorders, including those due to neurodegenerative diseases, traumatic brain injury (TBI), vascular disease, or abnormal brain development, share common features of memory-related pathology. Structural and functional deficits of synapses are at the core of the underlying pathophysiology, constituting a critical point of convergence in memory disorders. Memory therapeutics that target synaptic loss and dysfunction - that is, to slow, halt, or reverse progression of the disorders at the level of synapses, via synaptogenic molecular cascades such as those of protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) - possess universal therapeutic value for many forms of memory disorder. They may be useful either as standalone interventions for patients with memory disorders or as adjuncts to drugs that target the underlying pathology.

Fragile X syndrome (FXS) is caused by transcriptional silencing in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP), a repressor of dendritic mRNA translation. The lack of FMRP leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder that currently has no effective therapeutics. Fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase ε activator with pharmacological profiles of rapid mGluR desensitization, synaptogenesis, and synaptic maturation/repairing. Differences in the major FXS phenotypes, synapses, and cognitive functions were evaluated and compared among the age-matched groups. Long-term treatment with bryostatin-1 rescues adult fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in hippocampal brain-derived neurotrophic factor expression and secretion, postsynaptic density-95 levels, glycogen synthase kinase-3β phosphorylation, transformation of immature dendritic spines to mature synapses, densities of the presynaptic and postsynaptic membranes, and spatial learning and memory. Our results show that synaptic and cognitive function of adult FXS mice can be normalized through pharmacologic treatment and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation even after postpartum brain development has largely completed.

The 'vascular depression' hypothesis has recently attracted significant research attention, although the causal relationship between vascular-related injuries and depression has not been established. Here, we show that one episode of cerebral ischemia was sufficient to greatly increase the sensitivity of rats to potentially depressogenic events, evaluated at below-threshold intensities in the open space swim test. The induced 'ischemic depression' was lasting and sensitive to an acute administration of brain-derived neurotrophic factor or bryostatin-1, a relatively selective activator of protein kinase Cε, during the induction phase. Chronic treatment with bryostatin-1 (5 weeks) after the induction of depressive behavior reversed the depressive immobility and produced a lasting therapeutic effect, which remained effective 3 weeks after discontinuation of the treatment. Similar treatment with alaproclate, a selective serotonin reuptake inhibitor, in contrast, produced temporary relief from the depressive symptoms, with the therapeutic effect disappearing soon after the end of the treatment. The results strongly suggest that cerebral ischemia has a direct role in shaping the sensitivity of an individual to depressogenic events and that bryostatin-1-like agents may be developed as therapeutics for treating ischemic depression in humans.

Background: Modulation of synaptic functions holds great potential as therapeutic strategies to manage neurodegenerative disorders in which cognitive functions are usually impaired as a core symptom of the disorders. The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) and subtype 5 metabotropic glutamate receptors (mGluR5s) are critically involved in a variety of cognitive functions and deficits and their selective modulators may be developed into effective drugs for enhancing cognition and reducing cognitive deficits. Objective: This short review covers recent advances in research development of AMPAR and mGluR5 modulators as potential therapeutics for the treatment of cognitive impairment. Results/conclusion: Selective modulators of AMPARs and mGluR5s possess several advantages over the receptor agonists/antagonists as potential novel therapeutics for cognitive impairment. Positive allosteric modulators have potential therapeutic value in correcting the glutamatergic hypofunction...

Evidence is emerging that protein kinase C (PKC) plays a crucial role in the neural processing of memory information and that PKC deficits underlie certain types of memory impairment, including Alzheimer's dementia. Chronic activation of PKC isozymes with bryostatin-1 induces synthesis of the proteins that are involved in memory consolidation and, therefore, may represent a pharmacological strategy for antidementic and memory therapies. PKC isozymes are, however, sensitive to oxidants, whose generation is also increased by PKC activation. Oxidants may be responsible for some adverse effects with PKC activators, potentially limiting their antidementic and memory-enhancing "benefit". We investigated the effects of intravenous bryostatin-1, a potent PKC activator, and of its co-administration with oral alpha-tocopherol, a potent antioxidant, on spatial learning and memory. Bryostatin-1 at a chronic and intravenous dose of 10 microg/m2 (2 doses/week for 3 weeks) alone did not significantly affect the spatial learning and memory, but showed a synergistic effect when co-administered with alpha-tocopherol (60 IU/kg, orally and daily for 3 weeks), a potent lipid-soluble antioxidant and also a possible inhibitor of PKC in peripheral tissues. Acute administration of the same doses, however, did not have obvious influence on the learning and memory. These results provide support for the strategy of achieving memory-enhancing benefits with PKC activators and restricting their oxidant-related adverse effects with alpha-tocopherol co-administration. These agents, therefore, may hold significant potential as new, combined antidementic and memory therapeutics in the future.

Activity of protein kinase C (PKC) isozymes plays a critical role in various types of learning and memory. In addition, abnormal functions of PKC signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and dementia related to ischemic/stroke events. In preclinical studies, inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes has been found to enhance learning and memory and/or to produce antidementic effects. The PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognitive therapeutics and agents against dementia in the future.

Bryostatin‐1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin‐1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin‐1 exhibits additional important pharmacological activities. In preclinical studies bryostatin‐1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long‐term memory, restoration of stress‐evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin‐1 as a CNS drug should be further explored.

Dementia and depression are clinical symptoms commonly associated in patients. Emerging evidence suggests that the two diseases share many profiles in their development and underlying neural/molecular mechanisms. Thus, interest is raised in developing new classes of antidepressant agents with activity of cognitive enhancement. Here, we show that bryostatin-1, a protein kinase C substrate activator, at bilateral intracerebroventricular doses of 0.64 or 2 pmol/site, significantly enhanced learning and memory of rats in a spatial water maze task. When applied at the doses at which it exhibits memory-enhancing activity, bryostatin-1 showed a significant antidepressant activity, as determined in an open space swim test. Both effects were not observed when a smaller dose was administered and were largely eliminated by co-administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor. These results support the hypothesis that memory processing and mood regulation share common neural mechanisms. Restoring impaired mood regulation with antidepressant agents that also exhibit memory-enhancing activity may represent one of the new strategies in the fight against depression associated with memory impairments.

Depression and mood disorders are major public health concerns. Emerging evidence suggests that abnormal functions of protein kinase C (PKC) isozymes, ubiquitous in the central nervous system, may play a critical role in the pathogenesis of major depression and mood disorders. PKC activity and expression in the brain regions that are involved in mood regulation are reduced in suicide victims and are sensitive to stress-related damage. PKC isozyme dysfunction may contribute to mood dysfunction, while PKC activators exhibit antidepressant pharmacology. Restoration of PKC activity thus represents an important therapeutic goal in antidepressant therapy. PKC substrate activators, therefore, may have important therapeutic value for the treatment of depression, especially when fine-tuning of selective isoform activity can be effectively achieved pharmacologically. The success of antidepressant therapy with bryostatin-1-like agents that act on PKC signaling cascades depends on whether such agents at their effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC activities. Drug Dev. Res. 65:156–169, 2005. © 2005 Wiley-Liss, Inc.

Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic episodes and/or chronic hypoxia secondary to compromise of respiratory function.

Enhancement of memory acquisition and recall represents an important pharmacological goal in the treatment of cognitive disorders. In addition to its involvement in pH regulation, HCO3- reabsorption and CO2 expiration, carbonic anhydrase plays a crucial role in signal processing, long-term synaptic transformation and attentional gating of memory storage. Carbonic anhydrase dysfunction impairs cognition and is associated with mental retardation, Alzheimer's disease and aging. The pharmacological profile of carbonic anhydrase has been refined and specific activators have been developed. In this article, an integrated view of the involvement of carbonic anhydrase activity in synaptic plasticity and cognition will be presented, with particular focus on attentional gating of spatial learning and memory.

Stress in life is unavoidable, affecting everyone on a daily basis. Psychological stress in mammals triggers a rapidly organized response for survival, but it may also cause a variety of behavioral disorders and damage cognitive function. Stress is associated with biases in cognitive processing; some of the most enduring memories are formed by traumatic events. Our understanding of how cognition is shaped by stress is still relatively primitive; however, evidence is rapidly accumulating that the 'mature' brain has a great capacity for plasticity and that there are numerous ways through which pharmacological therapeutics could rescue cognitive function and regain cognitive balance. In this review, we discuss recent advances in our understanding of the interplay between stress and cognitive processes and potential therapeutic approaches to stress-related behavioral and cognitive disorders.

In anesthetized rats, stimulation of the arterial chemoreceptors excites reticulospinal vasomotor neurons of the nucleus rostroventrolateral reticularis of the medulla oblongata, via activating the neuronal NMDA receptors. Excitation of these neurons is responsible for reflex increases in sympathetic neuronal activity and arterial pressure. Additional doses (0.12–0.24 g/kg, i.v.) of urethane dose-dependently reduced the elevations in the discharge rate of reticulospinal vasomotor and sympathetic neurons and of arterial pressure, elicited by stimulating the carotid chemoreceptors with intra-carotid injections of sodium cyanide (100 nmol/10 μl), without affecting discharges of the carotid chemoafferents. Microiontophoresis of urethane onto the reticulospinal vasomotor neurons reversibly inhibited the excitation elicited by stimulation of the chemoreceptors and by iontophoretically applied L -glutamate. The results indicate that the suppression of chemoreflexes by excessive amount of urethane is central and one of its actions is blocking excitatory amino acid transmission onto these vasomotor neurons.

In vitro, clonidine (1, 10, or 30 microM) dose-dependently and reversibly inhibited tonically active pacemaker neurons that correspond to the relatively fast-conducting reticulospinal vasomotor neurons of the rostral ventrolateral reticular nucleus of the medulla oblongata in rats. The clonidine-induced membrane-hyperpolarizing response of these neurons was abolished by either tetrodotoxin, bicuculline, a GABAA receptor antagonist, or 4,4'-diisothiocyano-1,2'-disulphonic stilbene acid, a Cl- channel blocker. We conclude that the clonidine-induced inhibition of the pacemaker neurons of the rostral ventrolateral reticular nucleus is indirect, mediated by synaptic release of gamma-aminobutyric acid (GABA) or GABA-like substances, which activate Cl- channels of the pacemaker neurons of the rostral ventrolateral reticular nucleus.

Responses of reticulospinal vasomotor neurons, recorded in the rostral ventrolateral reticular nucleus of the medulla oblongata, to γ-aminobutyric acid (GABA) and cyanide microiontophoreses were examined during H + iontophoresis in anesthetized rats. Extracellular H + iontophoresis attenuated GABA-evoked decreases and enhanced cyanide-induced increases in the neuronal activity, but had no effect on the neuronal activity when applied alone. Opposite responses were produced during OH − iontophoresis. Similar effects were also observed on the glycine-evoked inhibition of these neurons during H + and OH − iontophoreses, suggesting that H + modulation of the GABA-evoked inhibition may not result from a specific action at the GABA receptor-channel complex. It is concluded that extracellular H + ions exert a modulatory action on responses of the reticulospinal vasomotor neurons to other neuro-active substances and may significantly contribute to hypoxic-ischemic cardiovascular regulation.

Evidence is accumulating indicating that some protein kinase C (PKC) isozymes play an essential role in various phases as well as types of learning and memory. Abnormal functions of PKC signal cascades in the brains have been found to represent one of the earliest changes in patients with Alzheimer's disease (AD) and other types of memory deficits, including those related to cerebral ischemic/stroke events. In preclinical studies, an inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of some PKC isozymes results in an enhancement of learning and memory and/or antidementic effects against memory disorders. PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity, including neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas, but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC isoform pharmacology may represent an attractive area for the development of cognition-enhancing agents and therapeutics against memory loss in the future.

In anesthetized rats, iontophoretic application of ATP excited the spinal cord-projection neurons in the rostral ventrolateral reticular nucleus of the medulla oblongata. The neuronal response to ATP was mimicked and then blocked by α,β-methylene-ATP, a metabolically stable ATP analogue, and the response was abolished by suramin. Microinjections of ATP (3–100 pmol) into the rostral ventrolateral medulla produced a powerful pressor response. The results suggest that ATP may function as a neurotransmitter or neuromodulator involved in medullary regulation of cardiovascular functions.

Inositol hexakisphosphate (IP6) was microinjected into the rostral venttrolateral reticular nucleus or iontophoresed onto reticulospinal sympathoexcitatory neurons of the nucleus in anesthetized rats. IP6 (5–500 pmol) induced a dose-dependent potent and prolonged elevation of arterial pressure which was mimicked by microinjection of ethyleneglycol-bis (β-aminoethylether) N,N,N′,N′-tetraacetic acid (EGTA), while myo-inositol was ineffective. Iontophoretic application of IP6 and EGTA excited the medullary sympathoexcitatory neurons but myo-inositol had no effect. Ihe effect of IP6 on firing rate of the sympathoexcitatory neurons was abolished by co-administration of Ca2+ ions onto these neurons. The results indicate that IP6 acts extracellularly to excite the medullary sympathoexcitatory neurons. The excitatory actions of IP6 may depend, at least in part, on a calcium-chelating action. Chelation of extracellular Ca2+ might be a physiological action of IP6.

Effects of age on depression vulnerability and antidepressant efficacy remain an important concern. Here, we show, by using a novel animal model of depressive behavior, that young rats (4 weeks old) are more vulnerable to the induction of depressive behavior than older ones (3, 6, and 14 months old). The induced depressive behavior in different ages of rats, however, was similarly sensitive to imipramine. A direct cerebroventricular administration of brain-derived neurotrophic factor was also sufficient to produce an antidepressant-like effect in the rats of different ages. These results suggest that although different ages of rats exhibit different sensitivity to the induction of depressive behavior, the induced depressive behavior may involve the same type of underlying abnormal neuropathophysiology in the brain and is sensitive to imipramine and brain-derived neurotrophic factor treatment.

Protein kinase C (PKC) is involved in synaptic remodeling, induction of protein synthesis, and many other processes important in learning and memory. Activation of neuronal protein kinase C correlates with, and may be essential for, all phases of learning, including acquisition, consolidation, and reconsolidation. Protein kinase C activation is closely tied to hydrolysis of membrane lipids. Phospholipases C and A2 produce 1,2-diacylglycerol and arachidonic acid, which are direct activators of protein kinase C. Phospholipase C also produces inositol triphosphate, which releases calcium from internal stores. Protein kinase C interacts with many of the same pathways as insulin; therefore, it should not be surprising that insulin signaling and protein kinase C activation can both have powerful effects on memory storage and synaptic remodeling. However, investigating the possible roles of insulin in memory storage can be challenging, due to the powerful peripheral effects of insulin on glucose and the low concentration of insulin in the brain. Although peripheral for insulin, synthesized in the beta-cells of the pancreas, is primarily involved in regulating glucose, small amounts of insulin are also present in the brain. The functions of this brain insulin are inadequately understood. Protein kinase C may also contribute to insulin resistance by phosphorylating the insulin receptor substrates required for insulin signaling. Insulin is also responsible insulin-long term depression, a type of synaptic plasticity that is also dependent on protein kinase C. However, insulin can also activate PKC signaling pathways via PLC gamma, Erk 1/2 MAP kinase, and src stimulation. Taken together, the available evidence suggests that the major impact of protein kinase C and its interaction with insulin in the mature, fully differentiated nervous system appears to be to induce synaptogenesis, enhance memory, reduce Alzheimer's pathophysiology, and stimulate neurorepair.

There is strong evidence that protein kinase C (PKC) isozyme signaling pathways are causally involved in associative memory storage. Other observations have indicated that PKC signaling pathways regulate important molecular events in the neurodegenerative pathophysiology of Alzheimer's disease (AD), which is a progressive dementia that is characterized by loss of recent memory. This parallel involvement of PKC signaling in both memory and neurodegeneration indicates a common basis for the origins of both the symptoms and the pathology of AD. Here, we discuss this conceptual framework as a basis for an autopsy-validated peripheral biomarker--and for AD drug design targeting drugs (bryostatin and bryologs) that activate PKC isozymes--that has already demonstrated significant promise for treating both AD neurodegeneration and its symptomatic memory loss.

The existence of links between Alzheimer's disease and diabetes is an important topic currently under active debate. Establishing such links if they exist and defining their common pathogenesis and pathophysiological mechanisms may lead to new concepts and research directions for the pharmacological treatment of Alzheimer's disease and diabetes. Alzheimer's disease is associated with peripheral and central insulin abnormalities. Cognitive capacities are often impaired in patients with diabetes. There are many mechanisms by which insulin-signaling abnormalities may affect clinical and pathological outcome of Alzheimer's disease. Insulin resistance and dysregulation of the degradation of neurotoxic amyloid and insulin appear at the core of the links between Alzheimer's disease and diabetes. Functions and expression of insulysin, an enzyme involved in the degradation of neurotoxic amyloid peptides and insulin, are usually impaired or reduced in Alzheimer's disease and diabetes. The increased occurrence of insulin resistance in Alzheimer's disease suggests that improving insulin effectiveness and insulysin activity may have therapeutic value in Alzheimer's disease patients and therefore is worth intensive investigation.

PKC plays an important role in many types of learning and memory. Evidence has been provided that PKC activation and translocation are induced in associative learning tasks. PKC inhibition, on the other hand, impairs learning and memory, consistent with the observations that transgenic animal models with a particular PKC isoform deficit exhibit impaired capacity in cognition. The dramatic impact of PKC pharmacology on learning and memory is further emphasized by a regulatory role of PKC isozymes in amyloid production and accumulation. Recent study reveals that PKC activation greatly reduces neurotoxic amyloid production and accumulation. PKC activators, therefore, may have important therapeutic values in the treatment of dementia, especially when fine-tuning of selective isoform activity can be effectively achieved pharmacologically, with further development of isozymes-specific agents. The success of antidementia therapy with agents that act on PKC signaling cascades depends on whether such agents at their effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC activities.

Vulnerability of females to depression among humans has not previously been reflected in animal models. Here, we show, by using a novel animal model of depression, that young female Wistar rats are clearly more vulnerable to depression induction than the males. This differential female vulnerability follows estrous cycle stages, is associated with cognitive impairment, and can be markedly transformed with sex hormones. Male hormone reduces vulnerability in females, whereas female hormone increases vulnerability in males. The induced depressive behavior in both sexes, however, is sensitive to imipramine and to the antagonism of the glucocorticoid receptors within a hormonal pathway previously implicated in human depression. Anisomycin, a protein synthesis inhibitor, eliminates the antidepressive effects of both antidepressants and male hormone but does not affect depression induction and estradiol-induced higher vulnerability. Moreover, direct cerebroventricular administration of brain-derived neurotrophic factor (BDNF), whose mRNA levels in the hippocampus and frontal cortex reach its lowest levels when estrogen levels are highest, is sufficient to rescue the antidepressive effects in the presence of the protein synthesis inhibitor. A selective enhancement of BDNF expression and/or BDNF signal cascades in the neural circuits controlling mood may represent an effective strategy for the development of novel antidepressants for both sexes, whereas blocking the gender-related higher vulnerability to potentially depressogenic events may lead to the development of specific antidepressants for the females.

Depression is characterized by a lack of "motivation" rather than a lack of "physical space" to move around. This study was designed to evaluate predictivity of an open space swimming test for antidepressant activity of various antidepressants in rats. Without drug treatment, rats showed a significant reduction in the distance moved (increased immobility) over successive trials in an open space water pool. Three major classes of antidepressants and a selective serotonin reuptake inhibitor (SSRI) were tested. Repeated treatment (10 mg/kg x 3 per day) of imipramine, a prototypical tricyclic antidepressant, iproniazid, a monoamine oxidase inhibitor, mianserin, an atypical antidepressant, and alaproclate, an SSRI, all significantly reduced the immobility. These results suggest that the open space swimming test is highly predictive of antidepressant action and is more sensitive to the drug treatments. The measurement is more objective than that of the forced swimming test and does not involve judging and scoring the animals' movement or lack of movement by investigators. The demonstrated effectiveness of three major types of antidepressants and an SSRI suggests that the effects on the test are not restricted to a particular underlying molecular mechanism of action. Thus, this swimming test shows promising potential as a screen for novel antidepressants and, perhaps, for revealing some of the underlying pathophysiology of depression.

A body of evidence emerging in antidepressant and antidementia research has revealed a convergence of molecular events known to regulate neuronal plasticity in learning and memory with molecular actions of drugs for the treatment of depression. Many antidepressants are reported to have positive impact on learning and memory. These include agents acting through monoaminergic neurotransmitter systems, non-monoaminergic transmitter systems, and hormones. On the other hand, agents that appear to have memory-enhancing or antidementia value are frequently found to exhibit antidepressant activity in patients and animal depression models. It is becoming clear that the comorbidity of depression and dementia does not occur by chance, but rather is an inevitable consequence of pathologic relationships between the conditions. Molecular mechanisms and cascades that underlie memory may be shared by mood regulation and are vulnerable to stress and injuries. This review focuses on recent findings regarding effects of a variety of agents on dementia and depression and their common molecular mechanisms as well as their differences. A better understanding of the key underlying molecular components whose changed activities have dramatic influences on mood and cognition may lead to the development of novel and more effective therapeutic agents for the treatment of depression and dementia. In this review, some of the recent findings that suggest novel therapeutic strategies are also highlighted.

In anesthetized and ventilated rats, activation of carotid chemoreceptors with intracarotid administration of 100 nmol sodium cyanide rapidly excited the spinal cord-projecting vasomotor neurons in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata and sympathetic nerves and increased arterial pressure. The chemoreflex sympathoexcitatory pressor responses were attenuated by an acute systemic administration of ethanol at 0.45 g/kg, but not at 45 mg/kg. The ethanol effects were observed at the level of RVL-spinal vasomotor neurons, in attenuating the neuronal responses to the chemoreflex excitation and direct iontophoresis of N-methyl-D-aspartic acid (NMDA) but without altering responses of the carotid sinus nerves to intracarotid cyanide. The effect of ethanol on the RVL neurons was further defined as blocking NMDA-evoked inward current in the corresponding spontaneously active RVL neurons in vitro. The results indicate that acute ethanol intoxication markedly influences NMDA receptor activation and arterial chemoreflexes. The relevance of the type of action to clinical hypertension in chronic and heavy drinkers is discussed.

The acute effects of systemic ethanol on reticulospinal sympathoexcitatory neurons were examined in vivo in anesthetized, paralyzed rats. Ethanol (0.45 g/kg, i.v.) potentiated the depressant effect of locally applied γ-aminobutyric acid (GABA) but attenuated the excitatory effect of l -glutamate. The baroreflex-mediated inhibition of these neurons and sympathetic nerve activity were partially depressed by the agent while aortic nerve activity and its sensitivity to changes in arterial pressure were not altered. These results suggest that systemic ethanol may markedly influence cardiovascular function by interfering in medullary GABAergic and glutamatergic transmissions involved in central control of the cardiovascular system.

A total of 45 cells with spinal projections, pulse-synchronous discharges, and extreme sensitivity to changes in arterial pressure were recorded in the retrofacial portion of nucleus paragigantocellularis lateralis (PGCL) in halothane-anesthetized rats. Every unit tested was inhibited by iontophoretic applications of gamma-aminobutyric acid (GABA), glycine, and taurine and excited by glutamate or the GABA receptor antagonist bicuculline methiodide. The inhibitory effect of GABA was antagonized by bicuculline methiodide but not by strychnine; the effect of glycine was eliminated by strychnine but unaffected by bicuculline. Iontophoretically applied bicuculline completely antagonized the time-locked reduction in unit activity resulting from increases in arterial pressure while strychnine was ineffective. 1-Glutamate, applied in a dose that produced a larger increase in the unit discharge rate than bicuculline, did not significantly alter the magnitude of the inhibition associated with increases in arterial pressure. It is concluded that GABA or a related substance mediates the inhibition of PGCL reticulospinal neurons resulting from the activation of arterial baroreceptors.