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Neural Regen Res. 2016 May; 11(5): 719–720.
PMCID: PMC4904452

Cross tolerance: a tread to decipher the code of endogenous global cerebral resistance

Ashish Sharma, M.Pharm.* and Rohit Goyal

A cell is a house to myriad biochemical reactions composed in a symphony of various pathways, both survival and apoptotic. Apoptosis is of fundamental significance to an organ by replacing weary and senile cells with juvenile cells. Survival pathways are provoked in such events working towards resistance to necrosis and to mitigate the damage. The disruption in physiological equilibrium between apoptotic and survival pathways results in loss of function. Pathological necrosis of neuronal cells, known as neurodegeneration is an umbrella term for a wide range of clinical disorders such as Alzheimer's disease, schizophrenia, Parkinson's disease, prion's disease and Huntington's disease. Current armamentarium of drugs, use of antipsychotics provide a symptomatic relief rather than a cure to pathology of the disorder. Thus a physiological approach for therapy is required to prevent the loss of neurons or most imperatively trigger neurogenesis plus augment the neuronal migration and survival. A protection through preconditioning is thought to be an endogenous defence mechanism preserved through the evolution, a mechanism that poses global resistance against detrimental injury.

Murry et al. (1986) reported in murine heart, the experimental preconditioning in the form of short ischemic episodes deliver protection against subsequent potentially lethal ischemia/reperfusion insult. This paradigm of preconditioning was consequently tested and reported successful in other vital organs such as heart, kidney and spinal cord. Kitagawa et al. (1991) standardized this paradigm in animal brain for the first time, known as brain ischemic preconditioning (BIP). Activation of immune system with sublethal doses of chemical toxins provides protection against succeeding chemical or hypoxic injury in vivo. The fundamental finding of the study at the time was that sub-lethal insult with a stressor protects cells from successive detrimental injury with same stressor. The paradigm of cross-tolerance states that one kind of stressor can induce protection or pose resistance against various kinds of stressors. Numerous pathways are instigated upon preconditioning; many of these pathways are common within different paradigms of preconditioning. For a detailed discussion on such common targets and detailed bibliography, please refer to (Sharma and Goyal, 2015). By the mechanistic paradigm of cross-tolerance, it might be safe to hypothesize that BIP may offer a protection to animal brain from such neurotoxins in experimental settings.

BIP provides early window of protection (immediately after revival and up to 24 hours) and second window of protection (peaks at 72 hours and wanes after 7 days), and are manifested by membrane receptor adaptations and genomic reprogramming respectively. The brain develops a latent-cerebroprotective phenotype 72 hours after BIP (Aysan and Turgut, 2010). The paradigm of BIP against chemically induced damage of neurons may put the whole concept of BIP effectors in perspective of chemically induced neurodegeneration. Understanding of common molecular targets responsible for resistance against neurodegeneration using different paradigms of experimental preconditioning might help to postulate new theories and mechanisms for advantageous strategies of therapy for neurological disorders. Extensive review of literature suggests that a transient occlusion of middle cerebral arteries as compared to sham counterparts, efficiently reduces the infarct size by a minimum of 50 % and diminishes neurological deficits after final injury by protracted occlusion. BIP in experimental settings show a quantified increase in por-survival hallmarks such as phosphorylated kinases. Inhibition of free radicals and reactive oxygen species, recruitment of heme oxygenase-1 and activation by phosphorylation of kinases such as mitogen activated protein kinase and extracellular signal regulated kinase (ERK 1 and 2) is observed in preconditioned tissues after BIP. Upregulation of trophins such as vascular endothelial growth factor and activation of pro-survival pathways such as phosphoinositide 3-kinase/kinase Akt (PI3K/Akt) by ischemic preconditioning are relevant to clinical strategies. Akt is a downstream biomolecule of PI3k, which is activated upon stimulation of receptor tyrosine kinase by growth factors. PI3k facilitates phosphorylation of phosphoinositide-phosphate 2 to phosphoinositide-phosphate 3, which in turn activates Akt by protein kinase 1 mediated phosphorylation directly at threonine 308 domain and indirectly at serine 473 domain. Akt imparts its protective effects by blocking or downregulating the activity of glycogen synthase kinase 3-beta (GSK-3β) and Bcl-associated death promoter. An extensive research by Dhodda et al. (2004) elucidated other major putative endogenous mediators of BIP, authors reported that BIP imparted protection by a 100% recruitment proinflammatory cytokines such as interleukins (IL-6 and IL-1β) and 70% of total recruitment of a chaperon, heat shock protein 72 (HSP72) was involved in BIP imparted protection. Trophins such as nerve growth factor and brain- derived neurotrophic factor (BDNF) are highly expressed and their receptors recover significantly after preconditioning. The pharmacological targets and trophins like insulin like growth factor, vascular endothelial growth factor, ERK, BDNF, Wnt/wingless glycoproteins, protein kinase-A and PI3K/Akt pathways have received much attention (Tihomir, 2008). As discussed in a review, lipopolysaccharide induced preconditioning shares same hallmarks with BIP (Cadet and Krasnova, 2009). Here authors discussed that stimulation of toll like receptors by sublethal doses of lipopolysaccharide upregulates various proteins and transcriptional factors such as B-cell lymphoma 2, and cyclic AMP-response element binding protein and nuclear transcriptional factors such as SMAD 1 and 7. Preconditioning by excitotoxin NMDA, provides a time- and dose/concentration- dependent neuroprotection against chemically induced neurodegeneration. Further investigation of the mechanism of NMDA preconditioning revealed that oxidative effects were curbed by inhibition of cyclic adenosine mono phosphate leading to a protective action of its response-element binding protein and subsequently induction of BDNF (Boeck et al., 2004). Overtime, other mechanisms of NMDA preconditioning were recognized to be Akt activation, GSK inhibition, protein 53 inhibition and B-cell lymphoma 2-associated death promoter phosphorylation. Increased expression of HSP72 and glucose regulated protein is also noticed, and these pathways are noticeably similar to BIP. Heat shock proteins are a set of chaperons that optimize protein folding and escort heavily damaged proteins to degradation sites. HSPs and HSP72 in particular is upregulated by preconditioning and reported to be protective in animals. HSP72 induced molecular events contribute to resistance from two major types of apoptosis: caspase-dependent apoptosis and caspase-independent apoptosis by inhibition of apoptosis-inducing factor.

The preservation of mitochondrial function seems to be the pivotal means of protection. It is observed in overwhelming number of reports that both ischemic and chemical preconditioning help preserve the mitochondrial function. GSK-3β is directly related to the modulation of mitochondrial permeability transition pore (mPTP) opening, which in turn is affected by numerous upstream biomolecules such as Wnt/wingless glycoproteins, Akt, mitogen activated protein kinase, protein kinase-C, ERK, adenosine receptors-type2 and mitochondrial ATP sensitive potassium channels. Protective outcomes of serine 9 phosphorylation of GSK-3β are well documented in relation to mPTP opening. mPTP opening results in ATP efflux and finally its depletion along with loss of mitochondrial integrity, which results in cell death. Serine 9 phosphorylation of GSK-3β guards against mPTP opening by increasing the threshold of mPTP opening and inhibiting its modulation by protein 53. Suppression of ATP transport within the matrix of mitochondria may be another way by which GSK-3β maintains mitochondrial integrity. There is a downregulation in cumulative transcriptional response after injury in a preconditioned brain as opposed to upregulated response after injury in an unprotected brain. This downregulation is not to be mistaken for a lack of response by preconditioned brain, rather a better reprogramming in response to injury (Stevens and Stenzel, 2006). This downregulation is only observed in genes/proteins that regulate metabolism, molecular transport and cell cycle control in different paradigms of preconditioning. This fact suggests that a protected brain exhibits lesser impairment in metabolism, lesser damaged proteins to be transported and lesser cell cycle abnormalities.

The recognition patterns of the receptors and thereupon pathways provoked by different stressors discussed here are strikingly similar to each other and justify the concept of cross-tolerance. BIP may prove to be an effective measure against chemically induced toxicity in vivo. It is a cascade of different pathways and cross-talk or the communication within the mediators plays a crucial and constitutive role in protection. Recent studies have focused on paradoxical role of GSK-3β by phosphorylation at different domains and role of HSP72. We have standardized the involvement of these two targets in protective effects of BIP against chemically induced toxicity in our laboratory (unpublished work), by using bilateral common carotid artery occlusion as protective measure against neurotoxin 3-nitropropionic acid.

Preconditioning is a remarkable tool to understand the mechanism of endogenous global resistance. This communication has discussed the common putative targets in different paradigms of preconditioning which modulate the different pathways accounting for protection. Along with exploration for culpable molecular targets, detailed investigations into both genetic and micro-environmental factors is required to further address this issue more specifically. Also, it is essential to test this paradigm and authenticate it in vivo within a wide range of neurotoxins validating its functional applicability to a broader spectrum of neurodegenerative disorders. It has now been known for quite some time that animal brain (also human) is capable of generating new neurons throughout the adult life, a process identified as adult neurogenesis. Etiopathology of most neurological diseases entail basic molecular pathways dysfunctions with disrupted adult neurogenesis. Another yet not verified and marginally a wild card hypothesis may be the connection of BIP to adult neurogenesis as a trigger, a factor which cannot be overlooked.


  • Antje W, Wolfgang W, Johannes W, Michael W, Johannes D, Jorg BS. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci. 2002;22:6401–6407. [PubMed]
  • Aysan D, Turgut T. Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection. Exp Transl Stroke Med. 2010;2:2. [PMC free article] [PubMed]
  • Boeck C, Ganzella M, Lottermann A, Vendite D. NMDA preconditioning protects against seizures and hippocampal neurotoxicity induced by quinolinic acid in mice. Epilepsia. 2004;45:745–750. [PubMed]
  • Cadet JL, Krasnova IN. Cellular and molecular neurobiology of brain preconditioning. Mol Neurobiol. 2009;39:50–61. [PMC free article] [PubMed]
  • Dhodda VK, Sailor KA, Kellie KB, Raghu V. Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. J Neurochem. 2004;89:73–89. [PubMed]
  • Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, Ueda H, Handa N, Kimura K, Kamada T. Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res. 1991;561:203–211. [PubMed]
  • Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136. [PubMed]
  • Sharma A, Goyal R. Experimental ischemic preconditioning: a concept to putative targets. CNS Neurol Disord Drug Targets. 2015;15:489–495. [PubMed]
  • Stevens SL, Stenzel-Poore MP Toll-like receptors and tolerance to ischaemic injury in the brain. Biochem Soc Trans. 2006;34:1352–1355. [PubMed]
  • Tihomir PO. Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev. 2008;88:211–247. [PubMed]

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