Neurotoxicity of Polyamines and Pharmacological Neuroprotection in Cultures of Rat Cerebellar Granule Cells

Spermidine attenuates the inhibitory effect of ethanol on NMDA-induced neurotoxicity

“…The finding that this NMDA effect was dramatically potentiated by spermidine is in good agreement with other studies in vitro showing that polyamines enhance NMDA receptor-mediated responses such as NMDA-induced currents (Lerma 1992;Peoples et al 1997;Popp et al 1998), 45 Ca 2+ influx (Grimwood et al 1996) and NMDA-induced neurotoxicity (Lombardi et al 1993;Tamura et al 1993;Sparapani et al 1997) and with studies in vivo indicating an involvement of NMDA receptors in spermine-and spermidine-induced CNS excitation (Singh et al 1990;120 Fig. 3 Spermidine potentiation of NMDA-induced neurotoxicity in the absence or presence of acutely added ethanol.…”

“…The polyamines spermine and spermidine are known as potent positive modulators of NMDA receptor activity, an event which was first demonstrated as increased binding of the open-channel blocker [ 3 H]MK-801 (Ransom and Stec 1988). Several reports indicate that these polyamines produce excitotoxic effects in cultured cerebellar granule cells (Lombardi et al 1993;Sparapani et al 1997;Segal and Skolnick 2000) and cortical neurons (Fahey et al 1993;Tamura et al 1993), whereas antagonists at the polyamine modulatory site have been shown to protect against glutamate-induced neurotoxicity in neuronal cell cultures (Tamura et al 1993;Beart et al 1995). The potentiating effect of polyamines on NMDA receptor functions is crucially dependent on the presence of NR1 subunits lacking insert N1 in their amino-terminal and is modulated by the type of NR2 subunits (for reviews see Johnson 1996).…”

Role of spermine in amyloid ?-peptide-associated free radical-induced neurotoxicity

“…Oxygen free radicals, particularly hydroxyl radical, were also reported to trigger induction of ODC activity, and the consequent increase of polyamine synthesis has been reported to have profound effects on neurogenesis and neurodifferentiation in the developing brain (Saito et al, 1997). The mechanism for increased endogenous polyamine levels in response to A␤-induced oxidative stress is unknown, and insight into this mechanism is confounded by conflicting reports that these compounds may cooperate in the recovery process of oxidatively damaged neurons or that they may play a direct role in neurodegenerative processes (Slotkin and Bartolome, 1986;Gilad and Gilad, 1991;Gilad et al, 1993;Farbiszewski et al, 1996;Sparapani et al, 1997). The blockade of polyamine biosynthesis at various pathways was reported to be neuroprotective against neuronal cell damage (Dempsey et al, 1988;Dogan et al, 1999a,b).…”

Pathogenic Factors in Vascular Dementia and Alzheimer’s Disease

“…Polyamines are toxic to cultures of brain cells [111]. This was mediated by their interaction with excitotoxic glutamate released by neurons.…”

“…Abnormal polyamine system activity is involved in the pathogenesis of AD [222]. Polyamines are toxic to cultures of rat cerebellar granule cells [223]. Polyamines damage the BBB [224].…”