Behavioural PharmacologyAgmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis
Introduction
Neuroinflammation is implicated in several neurodegenerative diseases, like, Alzheimer's disease, autism, Down syndrome, HIV dementia and demyelinating diseases (McGeer & McGeer, 1998, Akiyama et al., 2000, Vargas et al., 2005, Fischer-Smith et al., 2004, Mhatre et al., 2004) and may contribute to learning and memory deficits associated with these disorders. During early stages of Alzheimer's disease the greatest degree of neuroinflammation is found within temporal lobe regions involved in learning and memory (Cagnin et al., 2001). The brain is also vulnerable to constitutive defense responses, such as systemic inflammation. The systemic inflammation leads to generation of circulating cytokines, which impacts central nervous system (CNS) and causes neuroinflammation (Perry, 2004). It has been shown that intraperitoneal injection of lipopolysacharid (LPS) — a cell wall component of gram-negative bacteria-induces neuroinflammation, hippocampal apoptosis, cognitive impairment, learning deficits and even beta amyloid plaques generation in the hippocampus (Lee et al., 2008, Shaw et al., 2001).
Agmatine is a polycationic amine synthesized via decarboxylation of l-arginine by arginine decarboxylase (ADC). It was long been known to as an intermediate in polyamine metabolism of various bacteria, plants and a range of invertebrates (Tabor and Tabor 1984). Later it was discovered that agmatine, ADC and agmatinase are expressed in mammalian tissues (Li et al., 1994, Raasch et al., 1995). In mammalian brains agmatine exist in some regions such as hypothalamus, hippocampus, cortex, locus ceruleus, Raphe nucleus and forebrain (Halaris and Plietz, 2007). It seems that agmatine meets most of the criteria of a neurotransmitter/neuromodulator in the brain. It is synthesized, stored and released from specific network of neurons, is inactivated by energy dependent reuptake mechanism, is degraded enzymatically and binds with high affinity to α2 adrenergic and imidazoline (I1) receptors (Reis and Regunathan, 2000).
Exogenously administered to rodents, agmatine reverses pain induced by inflammation, neuropathy and spinal cord injury (Fairbanks et al., 2000). Agmatine has also been reported to have some neuroprotective effects against MPTP neurotoxicity (Gilad et al., 2005), spinal cord ischemia (Gilad and Gilad, 2000) and restraint-induced structural changes in the brain (Zhu et al., 2008). In PC12 cells, cerebellum and cultured hippocampal cell, it prevents glutamate and NMDA neurotoxicity (Zhu et al., 2003, Olmos et al., 1999, Wang et al., 2006). Additionally it is known to exert antidepressant, anxiolytic, anti-tumor cell proliferative and anticonvulsive effects (Halaris and Plietz, 2007).
Considering the deteriorative effects of LPS on memory and suggested neuroprotective effect of agmatine, this study was designed to investigate if agmatine can prevent memory loss and hippocampal apoptosis caused by LPS.
Section snippets
Animals
Adult male Wistar rats weighing 200–250 g were used. The animals were maintained at room temperature (25 ± 2 ºC) under standard 12–12 h light–dark cycle with lights on at 7:00 AM. Food and water were available ad libitum except for the times of experiments. Animal care was according to the NIH Guide for the Care and Use of Laboratory Animals.
Materials
LPS and agmatine sulphate were purchased from Sigma, USA, Western blot antibodies (caspase-3, beta-actin and secondary HRP-conjugated) were purchased from Cell
Results
Fig. 1 shows the results obtained from pre-training administration of saline, LPS or (and) agmatine administration on water maze spatial learning and memory. Fig. 1A shows the escape latency to the hidden platform during days 1–3 of training. One way ANOVA of the escape latency showed significant differences between groups in days 1–3 (day 1: P value = 0.0014, F(5,42) = 4.830; day 2: P value < 0.0001 F(5,42) = 17.550; day3: P value < 0.0001, F(5,42) = 16.911). Post hoc analysis by Tukey's test showed that
Discussion
The current study confirmed that LPS significantly impairs water maze learning and memory, as the escape latency and the traveled distance to the hidden platform were increased. The LPS-induced impairments were completely reversed by concurrent intraperitoneal administration of agmatine in doses 5 and 10 mg/kg. Since LPS and/or agmatine did not affect the swimming speed of the animals (data not shown) and their ability to find the visible platform( in cued version of water maze) the observed
Acknowledgement
This work was supported by a grant from Shiraz University of Medical Sciences, Shiraz, Iran.
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2023, Brain, Behavior, and ImmunityCitation Excerpt :For example, a single dose of LPS can induce deficits in several domains of learning and memory, including spatial memory, object recognition, and alternation performance (Tarr et al., 2011; Kranjac et al., 2012; Sparkman et al., 2005). Similar effects have also been reported in female mice as well as in rats, indicating that these results are reproducible in several species and both sexes (Sparkman et al., 2005; Shaw et al., 2001; Zarifkar et al., 2010). For instance, a single injection of 1 mg/kg LPS given to adult male Wistar rats impaired Morris water maze performance, as indicated by increased escape latency and greater total distance travelled relative to vehicle treated animals (Shaw et al., 2001).
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2022, European Journal of PharmacologyCitation Excerpt :Regarding the effect of agmatine on the memory of intact animals, there are several studies that have presented contradictory results. In the studies using the Morris water maze, intraperitoneal injection of agmatine during training and test days at 1, 5, 10, and 50 mg/kg doses [20 min before each daily session for six days] (McKay et al., 2002), 5 and 10 mg/kg doses [4 h before each daily session for four days] (Zarifkar et al., 2010), and 40 mg/kg dose [1 h before each daily session for four days] (Moosavi et al., 2012) were reported to have no effects on rats' reference spatial memory. In contrast, a recent study disclosed that agmatine treatment at 20 and 40 mg/kg doses [30 min before each daily session for four days] (Borikar et al., 2020) improved spatial learning and memory in mice.