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Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This study explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+]CSF) and red blood cells (RBCs) ([Mg2+]RBC) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements. Animals were assigned to either normal or low Mg diet for 30 - 45 days. Following this, animals maintained on low Mg diet were supplemented with various Mg compounds. [Mg2+]CSF and [Mg2+]RBC were measured at baseline and following Mg administration. Anxiety-like behavior and cognitive function were also evaluated. The present study showed that a short-term and moderate reduction in Mg dietary intake results in a significant decline in [Mg2+]CSF and [Mg2+]RBC and the emergence of anxiety-like behavior in comparison to animals maintained on normal Mg diet. Supplementation with SC/BW extract significantly elevated [Mg2+]CSF and improved animal performance in the novel object recognition test in comparison with animals maintained on reduced Mg intake and supplemented with various Mg compounds. These observations indicate that brain [Mg2+] is more sensitive to a short-term and moderate reduction in Mg dietary intake than previously thought and emphasizes the importance of dietary Mg in replenishing brain Mg2+ reserves. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies demonstrated that the inhibition of cholinergic supersensitivity through nicotinic antagonists and partial agonists can be used successfully to treat depressed patients, especially those who are poor responders to selective serotonin reuptake inhibitors (SSRIs). In our effort to develop novel antidepressant drugs, LF-3-88 was identified as a potent nicotinic acetylcholine receptor ( nAChR) partial agonist with subnanomolar to nanomolar affinities for β2-containing nAChRs ( α2 β2, α3 β2, α4 β2, and α4 β2*) and superior selectivity away from α3 β4 − ( Ki > 104 nmol/L) and α7- nAChRs ( Ki > 104 nmol/L) as well as 51 other central nervous system (CNS)-related neurotransmitter receptors and transporters. Functional activities at different nAChR subtypes were characterized utilizing 86Rb+ ion efflux assays, two-electrode voltage-clamp (TEVC) recording in oocytes, and whole-cell current recording measurements. In mouse models, administration of LF-3-88 resulted in antidepressive-like behavioral signatures 15 min post injection in the SmartCube® test (5 and 10 mg/kg, i.p.; about 45-min session), decreased immobility in the forced swim test (1-3 mg/kg, i.p.; 1-10 mg/kg, p.o.; 30 min pretreatment, 6-min trial), and decreased latency to approach food in the novelty-suppressed feeding test after 29 days chronic administration once daily (5 mg/kg but not 10 mg/kg, p.o.; 15-min trial). In addition, LF-3-88 exhibited a favorable profile in pharmacokinetic/ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) assays. This compound was also shown to cause no mortality in wild-type Balb/CJ mice when tested at 300 mg/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression. [ABSTRACT FROM AUTHOR]

Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology. [ABSTRACT FROM AUTHOR]

There is a need for antidepressants with novel mechanisms of action. One approach has been to develop compounds that inhibit reuptake of all three monoamines in the central nervous system, for example DOV216,303. Differential reinforcement of low-rate (72-s) responding is a behavioral test that is predictive of antidepressant-like properties. The effects of antidepressant compounds belonging to multiple classes, the anxiolytic diazepam and the antipsychotic haloperidol, were assessed in the DRL-72s task. Subsequently, the antidepressant-like properties of acute DOV216,303 were assessed. The selective serotonin reuptake inhibitor fluvoxamine, the preferential norepinephrine reuptake inhibitor desipramine and the tricyclic antidepressant imipramine exhibited antidepressant-like properties in the DRL-72s task. The atypical antidepressant bupropion, which inhibits dopamine and norepinephrine reuptake, and the selective dopamine transporter inhibitor GBR12909, changed reinforcement and response rates and inter-response time distribution in an opposite direction compared with the antidepressant compounds tested. The antipsychotic haloperidol exhibited antidepressant-like properties by increasing reinforcement rate, but failed to alter inter-response time distribution. Diazepam did not change reinforcement or response rates or inter-response time distribution. The triple reuptake inhibitor DOV216,303 significantly enhanced reinforcement rate at one intermediate dose, but exhibited similar effects as bupropion and GBR12909 on inter-response time distribution. The studies identified limited antidepressant-like properties of the triple reuptake inhibitor DOV216,303, likely due to dopamine transporter inhibition counteracting the effects of norepinephrine and serotonin transporter inhibition. [ABSTRACT FROM PUBLISHER]