Table 1.

HSPs involved in haemorrhagic stroke

HSPs		Pathophysiological processes	Potential mechanisms	The induction location	Effect and roles	Related agents	Reference
Subarachnoid haemorrhage
HSP70 (including GRP78)		Cerebral vasospasm, neural cell apoptosis, immunoreaction and inflammation	Refold protein, degrade damaged proteins, inhibit apoptosis, mediate BBB disruption and cell death via aberrant proteolysis	Bilateral neocortex, hippocampus, thalamus, septum, hypothalamus, caudoputamen and basal forebrain	Neuroprotective molecule, significant marker for cellular stress or damage; crucial predictor of poor prognosis; blood biomarker for the early differential diagnosis of haemorrhagic stroke and ischemic stroke	Geranylgeranylacetone, modified HSP70 proteins (eg TAT‐Hsp70), valproic acid, atorvastatin,	12, 14, 15, 16, 17, 22, 24, 25, 28, 31, 33, 34, 35, 36, 37, 38, 40, 41, 50, 51, 52, 53, 54, 55, 56, 57, 58, 96, 97, 98
HO‐1		Cerebral vasospasm, lipid peroxidation	Metabolize haeme, remove haeme and iron, diastolic vascular smooth musclea	Microglia and cerebral blood vessels	Possible neuroprotective moleculeb; marker of cellular stress and damage in infarcted regions	Nicaraven, argon, carnosol, ebselen and CGS26393, HO‐1 protein combined with protein transduction domains	14, 39, 40, 61, 62, 63, 64, 65, 66, 70, 71, 99, 100, 101
HSP20 and HSP27		Cerebral vasoconstriction, apoptosis pathway	Solubilize misfolded proteins and hinder their aggregation, suppress cell death signaling and protect neurons against ischemic injury	Astrocytes in the ischaemic zone and the ischaemic penumbra	Important molecules in cerebral vasoconstriction without ATP necessarily involved in the function	AZX100	14, 28, 40, 73, 74, 75, 76, 77, 78
HSP90		Apoptosis, inflammation, and BBB destruction	Stabilize and promote the function of P2X7 receptor, which is abundant in the nervous system and is associated with the pathophysiological process of inflammation and oxidative stress in EBI	Microglia and neurons of the hippocampus	Neurotoxic factor in the development of EBI	17‐allylamino‐17‐demethoxygeldanamycin, A438079	79, 80, 81, 82, 83, 84, 85
Intracerebral haemorrhage
HO‐1		Inflammation, oxidative stress and cytotoxicity	Increase oxidative stress, accelerate the accumulation of iron overload, promote inflammation and increase secondary injury	Microglia and cerebral blood vessels	Possible harmful moleculeb	Haemin, nicotinamide mononucleotides, minocycline	14, 20, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 134, 144, 145, 146
HSP70	GRP75	Neural cell apoptosis, immunoreaction	Inhibit inflammation and neuronal apoptosis	Mainly located in mitochondria, reduced after intracerebral haemorrhage	Neuroprotective molecule	Minocycline, geranylgeranylacetone, geldanamycin, Di Dang Tang	36, 135, 136, 137, 138, 139, 140, 147, 148, 149, 150
	GRP78	Neural cell apoptosis	Inhibit neuronal apoptosis	Mainly located in endoplasmic reticulum	Neuroprotective molecule

Abbreviations: BBB, blood‐brain barrier; EBI, early brain injury; GRP75, glucose‐regulated protein 75; GRP78, glucose‐regulated protein 78; HO‐1, haeme oxygenase‐1; HSP, heat shock protein; TAT, N‐terminal transactivator of transcription.

^aCarbon monoxide, one of the haeme metabolite, can up‐regulate soluble guanylyl cyclase, which contributes to cyclic guanosine monophosphate accumulation and subsequently leads to vascular smooth muscle relaxation.

^bThe role of HO‐1 is still controversial, the overall effect of HO‐1 in SAH and ICH tends to be protective and harmful respectively.