Kaempferol is a polyphenol of the flavonol family of flavonoids. Therefore, kaempferol’s chemical structure (Figure 1) is closely related to other flavonols with beneficial chemotherapeutic properties, like quercetin ^[1][2][1,2]. Kaempferol, like other flavonoids, is largely present as a glycoside derivative in plants. Apart from the most abundant glycoside derivatives, kaempferol-3-O-glucoside (astragalin), kaempferol-3,7-dirhamnoside (kaempferitrin) and kaempferol-3-O-rutinoside (nicotiflorin) [3], many other bioactive kaempferol glycosides have been found in plants, like kaempferol 3-O-[(6-O-E-caffeoyl) β-D-glucopyranosyl-(1→2)]-β-D-galactopyranoside-7-O-β-D-glucuropyranoside, kaempferol 3-O-[(6-O-E-p-coumaroyl)-β-D-glucopyranosyl-(1→2)]-β-D-galactopyranoside-7-O-β-D-glucuropyranoside and kaempferol 3-O-[(6-O-E-feruloyl)-β-D-glucopyranosyl-(1→2)]-β-D-galactopyranoside-7-O-β-D-glucuropyranoside ^[4][5][4,5].

Kaempferol and its glycoside derivatives can be found in a variety of plants and plant-derived food products, such as spinach, kale, cabbage, chives, lentils, tea, broccoli, apples, and Ginkgo biloba, among others ^{[5][6][7][8][9]}[5,6,7,8,9]. The plasma concentrations of total flavonoid metabolites vary from 0 to 2.0 μM, with an intake of 50 mg aglycone equivalents in humans, although isoflavones can reach higher concentrations, as well as metabolites generated by the gut ^[10][11][10,11]. After food intake, bacterial enzymes and enterocyte β-glucosidases of the intestine hydrolyze flavonoid glycosides to their aglycones ^[12][13][12,13]. In addition, flavonoid aglycones undergo methylation and glucuronidation in the intestine [14] and their metabolites are further metabolized by the liver [12]. It should be noted that glial cells can also catalyze in vitro oxidation and conjugation of flavonoids with reduced glutathione (GSH) [15]. Although flavonoid metabolites are still bioactive as cellular antioxidants, most of these metabolites have been shown to have lower chemical antioxidant potency than the aglycone flavonoid ^[16][17][18][16,17,18], and this also seems to be the case of kaempferol [19]. Furthermore, the kaempferol glycosides most abundant in plants (astragalin, kaempferitrin, and nicotiflorin) have poorer antiproliferative activity than kaempferol [20]. Therefore, the medicinal use of kaempferol requires us to pay special attention to the administration route. Also, if the concentration of blood kaempferol needed in therapeutic treatments of brain damage is higher than 1–2 μM, instead of oral supplementation, other methods of administration must be used, i.e., intravenous (IV) or microencapsulation delivery.

The redox potential of kaempferol, ~0.39 V ^[21][22][21,22], indicates that this compound is a chemical antioxidant. Furthermore, kaempferol, as well as other flavonoids, can form stable radicals that may act as reactive species scavengers [23]. The acceptance of flavonoids as cellular antioxidants is largely based upon their ability to scavenge hydroxyl radicals, superoxide anion, lipid peroxides, and peroxynitrite ^{[23][24][25][26][27][28]}[23,24,25,26,27,28]. The number of hydroxyl groups in the B-ring and the presence of a carbonyl group in C4 of the C-ring are particularly relevant for the scavenging of these reactive oxygen species (ROS) [27]. Of note, the flavonoids that most efficiently scavenge hydroxyl radicals are flavonols [23], i.e., the family of flavonoids to which kaempferol belongs (Figure 1). Moreover, compared with other phenols and flavonoids, kaempferol has a relatively high peroxynitrite scavenger activity ^[29][30][29,30]. Another property of flavonoids relevant for their role as cellular antioxidants is their liposolubility. The inhibition of lipid peroxidation by flavonoids correlates with their partition coefficient between n-octanol and water, because flavonoids need to incorporate into the lipid bilayer to trap the species initiating lipid oxidation radical chains ^[31][32][31,32]. Indeed, flavonoids act as hydrogen donors in the reaction with the peroxyl radical produced in the oxidation of fatty acids [33]. It has been shown that the higher solubility in water can account for the lower potency of flavonoid glycosides as inhibitors of lipid peroxidation compared with their respective flavonoid aglycones ^[34][35][34,35]. In addition, the solubility of flavonoids in lipid bilayers favors its uptake by cells and tissues. Notably, kaempferol is one of the flavonoids with a higher lipid/water partition coefficient [36].

2. Kaempferol Administration Efficiently Prevents Brain Damage Induced by Ischemic Insults

The brain ischemic insult elicited by a stroke episode is a major health problem in humans, as they often cause death or chronic disability. Ischemia stroke is the most frequent type of cerebrovascular stroke ^[37][38][49,50]. The transient blockade of blood flow produces rapid tissue damage in the so-called ischemic core. The rapid metabolic energy falls, leading to the depolarization of cell membranes, which causes rapid necrosis in the ischemic core. Later, the brain damage extends into the peri-infarct region ^[39][51]. Restoration of blood flow (reperfusion) is necessary, but this can aggravate brain damage ^[40][41][52,53], as it leads to disability and a high morbidity in patients due to irreversible brain damage. The excessive production of ROS and reactive nitrogen species, excitotoxicity, and brain inflammation are implicated in the neuronal damage during a brain ischemia-reperfusion injury ^[42][54]. Of note, oxidative stress-mediated inflammation and apoptosis are considered to play a crucial role in brain damage associated with ischemia-reperfusion episodes ^[43][44][55,56]. Glutamate excitotoxicity ^[39][45][46][51,57,58], oxidative stress ^[39][47][48][51,59,60], edema and inflammation ^[39][46][51,58], activation of matrix metalloproteinases ^{[49][50][51][52]}[61,62,63,64], and apoptosis ^[48][53][54][60,65,66] contribute to spreading the brain damage to the peri-infarct region. The slow time course of this phase opens a temporal window for neuroprotective interventions. Protective effects of different flavonoids against the ischemic brain damage produced by cerebral ischemia have been shown in many studies with experimental animals, reviewed in [1]. As noted in [1], these studies showed that the efficiency of protection against brain damage in transient cerebral ischemia largely varies between different flavonoids and depends on the administration route and doses. For example, the neuroprotective action of Ginkgo biloba extract EGb761, which is rich in kaempferol, in brain ischemia models seems to be dependent on the expression of heme oxigenase-1 ^[55][67], an enzyme that is modulated by kaempferol in different cells ^[56][57][68,69]. Also, nicotiflorin (kaempferol-3-O-rutinoside) has neuroprotective effects in permanent ^[58][70] and transient ^[59][71] models of rat cerebral ischemia. To study the effect of the IV administration of kaempferol on brain damage induced by ischemia-reperfusion, first thwe researchers sesetup a rat model of transient focal ischemia using a new surgical technique of middle cerebral artery occlusion (MCAO) by selective endovascular placement of a guide-wire ^[60][72]. The Ouresearchers' study published in 2007 ^[61][41] has been, to the best of the ouresearchers' knowledge, the first work that reported on the role of kaempferol administration in the protection against the brain damage caused by transient cerebral ischemia. The main results and conclusions obtained in this work are summarized next (Figure 2 and Figure 3).