The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice

Abstract

Diisopropyl fluorophosphate (DFP) causes neurotoxicity related to an irreversible inhibition of acetylcholinesterase (AChE). Management of this intoxication includes: (i) pretreatment with reversible blockers of AChE, (ii) blockade of muscarinic receptors with atropine, and (iii) facilitation of GABAA receptor signal transduction by benzodiazepines. The major disadvantage associated with this treatment combination is that it must to be repeated frequently and, in some cases, protractedly. Also, the use of diazepam (DZP) and congeners includes unwanted side effects, including sedation, amnesia, cardiorespiratory depression, and anticonvulsive tolerance. To avoid these treatment complications but safely protect against DFP-induced seizures and other CNS toxicity, we adopted the strategy of administering mice with (i) small doses of huperzine A (HUP), a reversible and long-lasting (half-life Ϸ5 h) inhibitor of AChE, and (ii) imidazenil (IMI), a potent positive allosteric modulator of GABA action selective for ␣5-containing GABAA receptors. Coadministration of HUP (50 g/kg s.c., 15 min before DFP) with IMI (2 mg/kg s.c., 30 min before DFP) prevents DFP-induced convulsions and the associated neuronal damage and mortality, allowing complete recovery within 18 -24 h. In HUP-pretreated mice, the ED50 of IMI to block DFP-induced mortality is Ϸ10 times lower than that of DZP and is devoid of sedation. Our data show that a combination of HUP with IMI is a prophylactic, potent, and safe therapeutic strategy to overcome DFP toxicity.GABAA receptor ͉ neurotoxicity

Neurosteroids reduce social isolation-induced behavioral deficits: a proposed link with neurosteroid-mediated upregulation of BDNF expression

“…However, 5α-reductase fails to change in GABAergic neurons of the reticular thalamic nucleus, central amygdala, cerebellum, or in the medium spiny neurons of the caudatus and putamen (Agis-Balboa et al, 2007). The decrease of 5α-reductase in the above-mentioned brain areas resulted in a reduction of allopregnanolone levels (Pibiri et al, 2008). …”

Metabolomics Coupled with Proteomics Advancing Drug Discovery toward More Agile Development of Targeted Combination Therapies

“…Because of the complexity of medicine, treatment protocols should be carefully designed, and prescriptions must be carefully developed to successfully fight a given disease. A growing body of evidence has demonstrated that treating illnesses such as human acute promyelocytic leukemia (5,6), cancer (7), HIV (8), chronic hepatitis C (9), and diabetic nephropathy (10) with treatment regimens that use multiple drugs for combination therapy and related mechanisms usually amplifies the therapeutic efficacy of each agent, yielding maximum therapeutic efficacy with minimal adverse effects (11). Such developments represent a triumph for modern medicine and provide fertile ground for modern drug development (12,13).…”

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

“…HUP-A has been used for centuries in herbal medicine to treat inflammatory and other diseases (10,12), has demonstrated effectiveness in inhibiting hypersensitivity triggered by peripheral neuropathy (20), and has been studied in phase II clinical trials for Alzheimer's disease in the United States (11). We tested whether HUP-A regimens might translate into an effective and safe therapy for neuropathic pain following SCI in adult female rats (21)(22)(23).…”