The Limitless Stack (UNDER CONSTRUCTION)

Three compounds act on acetylcholine at different points. CDP-choline supplies the choline it is made from [17], and pramiracetam acts on the transport of choline across the blood-brain barrier [4]. Nefiracetam stimulates acetylcholine release in the frontal cortex and raises the activity of choline acetyltransferase, the enzyme that makes it [20], and potentiates the α4β2 nicotinic receptors acetylcholine acts on [1].

Two compounds strengthen the response to glutamate, each at a different receptor. TAK-653 potentiates AMPA receptors only while glutamate is bound, amplifying synaptic signalling that is already under way [6]. Nefiracetam potentiates NMDA receptors through protein kinase Cα, enhancing glycine binding and largely removing the channel's magnesium block [2].

Three compounds favour the lasting strengthening of a synapse after it is used. Nefiracetam enhances long-term potentiation in the hippocampus through CaMKII, PKCα and the phosphorylation of AMPA receptors [3]. BPN14770 let a weak stimulus produce long-lasting potentiation in hippocampal slices from mice carrying the human PDE4D [14], and J-147 helped potentiation form in rat hippocampal slices [21].

BPN14770 inhibits PDE4D most strongly once PKA has activated the enzyme, so it acts where cAMP signalling is already under way [13]. In mice carrying the human enzyme it raised brain cAMP and, after two weeks, phosphorylation of the transcription factor CREB in the hippocampus [14]; a PKA inhibitor blocked its memory effects [22].

Four compounds raise the growth factor BDNF and a fifth acts on its receptor. TAK-653 raises BDNF in cortical neurons [7], BPN14770 raised it in the hippocampus with repeated dosing [14], J-147 raises hippocampal BDNF and NGF [16], and NSI-189 raised BDNF and stem cell factor in oxygen- and glucose-deprived hippocampal cultures [10]. ACD856 works on the receptor side: it makes the Trk receptors respond more strongly to BDNF, NGF and NT-3 [11].

NSI-189 was selected for making human hippocampus-derived neural stem cells proliferate [8]. In irradiated rats it raised the number of newly born granule neurons in the hippocampus [9].

BPN14770 raised phosphorylated synapsin and the postsynaptic protein PSD95 in the hippocampus [14], and J-147 restored synaptic proteins in Alzheimer's-model mice [21]. In cultured cells ACD856 largely prevented the loss of the synaptic protein SNAP25 caused by amyloid-β and lengthened the neurites grown in response to NGF [12]. NSI-189 increased the neurite marker MAP2 in the hippocampus and cortex of rats after stroke [10].

CDP-choline is the direct precursor of phosphatidylcholine, the main phospholipid in cell membranes. In animal models of cerebral ischaemia it also slows membrane breakdown by inhibiting phospholipases [17].

J-147 partly inhibits the mitochondrial ATP synthase, raises whole-cell ATP and activates AMPK through the calcium-sensing kinase CAMKK2 [15]. AMPK then inhibits ACC1, which raises acetyl-CoA in neurons and the acetylation of histone H3, a mark linked to memory formation [23]. ACD856 kept ATP levels up in cortical neurons deprived of glucose and pyruvate [12].

PRL-8-53 potentiates apomorphine-induced gnawing, a dopamine-dependent behaviour, without blocking monoamine oxidase [18]. In animals it also partly inhibits serotonin and produces a cholinergic response, without amphetamine-like stimulation [19].

PRL-8-53 improved the retention of verbal information in people, with a slight improvement in its acquisition; visual reaction time and motor control did not change [19]. In rats it promoted conditioned avoidance learning and maze performance [18].