Diphenhydramine-induced amnesia is mediated by Gi-protein activation

Galeotti, Nicoletta; Bartolini, A.; Ghelardini, Carla

doi:10.1016/j.neuroscience.2003.08.005

Cited by 16 publications

(14 citation statements)

References 28 publications

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“…Knockdown of RyR2 produced memory disruption of intensity comparable to that induced by amnesic drugs such as the ␣2-adrenoceptor agonist clonidine (Galeotti et al 2004a) and the antihistamine diphenhydramine (Galeotti et al 2003), indicating the importance of the integrity and functionality of the type 2 RyR isoform for the memory processes in a mouse passive avoidance task. In agreement with our results, the importance of Figure 7.…”

Section: Discussionmentioning

confidence: 91%

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

Galeotti¹,

Quattrone²,

Vivoli³

et al. 2008

Learn. Mem.

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The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003-9 nmol per mouse intracerebroventricularly [i.c.v.]) ameliorated memory functions, whereas the RyR antagonist ryanodine (0.0001-1 nmol per mouse i.c.v.) induced amnesia in the mouse passive avoidance test. The role of the type 1, 2, and 3 RyR isoforms in memory processes was then evaluated by inhibiting the expression of the three RyR proteins in the mouse brain. A selective knockdown of the RyR isoforms was obtained by the i.c.v. administration of antisense oligonucleotides (aODNs) complementary to the sequence of RyR1, RyR2 and RyR3 proteins, as demonstrated by immunoblotting experiments. RyR1 (5-9 nmol per mouse i.c.v.) knockdown mice did not show any memory dysfunction. Conversely, RyR2 (1-7 nmol per mouse i.c.v.) and RyR3 (1-7 nmol per mouse i.c.v.) knockdown animals showed an impairment of memory processes. This detrimental effect was temporary and reversible, disappearing 7 d after the end of the aODN treatment. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous mobility and inspection activity, as revealed by the hole-board test. In conclusion, the lack of any involvement of cerebral RyR1 was demonstrated. These findings also showed the involvement of type 2 and type 3 RyR in the modulation of memory functions identifying these cerebral RyR isoforms as critical targets underlying memory processes.

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Section: Discussionmentioning

confidence: 91%

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

Galeotti¹,

Quattrone²,

Vivoli³

et al. 2008

Learn. Mem.

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show abstract

“…Diphenhydramine overdose modulates the central nervous system (CNS) functions in a manner that may result in toxicosis (Wahl, 2005;Skidgel and Erdos, 2006;Scharman et al, 2006). Diphenhydramine enhances morphine-induced hyperactivity in mice (Sansone et al, 1987) and causes amnesia in mice (Galeotti et al, 2003). Mice or rats pretreated with relatively high protective doses of diphenhydramine (≥30 mg/kg, intraperitoneally or subcutaneously) prior to intoxication with anticholinesterases manifested nervousness, jumping behavior and hyperactivity (Mohammad et al, 1987;1989;Faris and Mohammad, 1996a;.…”

Section: Introductionmentioning

confidence: 99%

Acute Toxicity and Neurobehavioral Effects of Diphenhydramine in Chicks

2012

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The present study was undertaken to examine the acute toxicity (LD50) and neurobehavioral manifestations in the open-field activity and tonic immobility tests in 7-14 day-old chicks treated with the H1-receptor antagonist diphenhydramine. Plasma and whole brain cholinesterase activities were also determined in the chicks. The LD50 of diphenhydramine in chicks was 49.3 mg/kg, intramuscularly (i.m.). The signs of diphenhydramine toxicosis in the chicks which appeared within one hour after injection included excitation, jumping, whole body tremor, ataxia, gasping, frequent defecation, paralysis and recumbency. Fifteen minutes after i.m. injection, diphenhydramine at 2.5 and 5 mg/kg decreased the general locomotor activity of the chicks in the 5-min open-field activity test, as seen by a significant increase in the latency to move from the center of the open-field arena and decreases in the numbers of lines crossed and escape jumps in comparison with control values. Diphenhydramine significantly decreased the frequencies of pecking and defecation only at 5 mg/kg when compared with respective control values. Diphenhydramine treatments at 2.5 and 5 mg/kg also significantly increased the durations of tonic immobility of the chicks and decreased their whole brain cholinesterase activity by 33 and 30%, respectively, in comparison with the control values. In conclusion, the data suggest that diphenhydramine induces central nervous system depression in chicks at doses below the LD50 value of the drug which is reported here for the first time.

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“…ICV administration was performed under ether anesthesia, according to the method described by Galeotti et al. [40].…”

Section: Methodsmentioning

confidence: 99%

“…Six mice were used for each dose; control mice were injected with only 0.1% BSA in water to ensure that symptoms were not due to experimental conditions. ICV administration was performed under ether anesthesia, according to the method described by Galeotti et al [40].…”

Section: Purification Of Htxmentioning

confidence: 99%

Hemitoxin, the first potassium channel toxin from the venom of the Iranian scorpionHemiscorpius lepturus

et al. 2008

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Hemitoxin (HTX) is a new K+ channel blocker isolated from the venom of the Iranian scorpion Hemiscorpius lepturus. It represents only 0.1% of the venom proteins, and displaces [125I]α‐dendrotoxin from its site on rat brain synaptosomes with an IC50 value of 16 nm. The amino acid sequence of HTX shows that it is a 35‐mer basic peptide with eight cysteine residues, sharing 29–69% sequence identity with other K+ channel toxins, especially with those of the αKTX6 family. A homology‐based molecular model generated for HTX shows the characteristic α/β‐scaffold of scorpion toxins. The pairing of its disulfide bridges, deduced from MS of trypsin‐digested peptide, is similar to that of classical four disulfide bridged scorpion toxins (Cys1–Cys5, Cys2–Cys6, Cys3–Cys7 and Cys4–Cys8). Although it shows the highest sequence similarity with maurotoxin, HTX displays different affinities for Kv1 channel subtypes. It blocks rat Kv1.1, Kv1.2 and Kv1.3 channels expressed in Xenopus oocytes with IC50 values of 13, 16 and 2 nm, respectively. As previous studies have shown the critical role played by the β‐sheet in Kv1.3 blockers, we suggest that Arg231 is also important for Kv1.3 versus Kv1.2 HTX positive discrimination. This article gives information on the structure–function relationships of Kv1.2 and Kv1.3 inhibitors targeting developing peptidic inhibitors for the rational design of new toxins targeting given K+ channels with high selectivity.

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Diphenhydramine-induced amnesia is mediated by Gi-protein activation

Abstract: These results suggest the important role played by the Gi 1 -and Gi 2 -protein pathway in the transduction mechanism involved in the impairment of memory processes produced by the H 1 -antihistamine diphenhydramine.

Cited by 16 publications

References 28 publications

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

Acute Toxicity and Neurobehavioral Effects of Diphenhydramine in Chicks

Hemitoxin, the first potassium channel toxin from the venom of the Iranian scorpionHemiscorpius lepturus

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