Table 3.

Lipid systems affected by the CNS disorders and injuries

Disorder/injury	Symptoms/pathologic features	CNS region(s) affected	Mechanism of damage	Possible Treatments
Alzheimer Disease [10]	Memory loss/dementia Difficulties in communicating Problems learning, thinking, reasoning Difficulty with familiar tasks Disorientation Amyloid plaques and tau protein aggregation [13,14]	Amygdala Hippocampus Cerebral cortical areas controlling reasoning, learning, and language	Altered cholesterol [104] and lipid [105] homeostasis APP cleavage in lipid rafts [9] DHA levels ↓; upregulation of PLA2, increased lipid peroxidation [21,25,106] sPLA2-IIA expression increased [20]	Ganglioside treatments prevent neuronal death [25] ApoE protects against oxidative injury by mediating Aβ [105] Statins [16]
Parkinson’s Diseases [27]	Movement disorder Resting tremors Muscle rigidity Bradykinesia (slow movements) Impaired posture, balance, coordination Lewy bodies/α-synuclein aggregates	Substantia nigra	Although a direct role of PLA2 in PD is not yet clearly demonstrated, cPLA2 knock out mice showed protection against MPTP toxicity [25] PUFAs promote α-synuclein aggregation [27]	PLA2 inhibition [25] Ganglioside treatments [25] Quinacrine [25]
Niemann-Pick Disease [30,31,33]	Type A: progressive loss of early motor skills, early fatality typically within the first few Years	Lysosomal storage disorder that leads to SM and cholesterol accumulation.	Type A: <1% of normal A-SMase activity leads to lysosomal sphingomyelin accumulation	Enzyme replacement was shown to be effective in a mouse model for Type B [108].
	Type B: enlarged liver, spleen; and respiratory problems		Type B: <10% of normal A-SMase	D609, a SM synthase inhibitor may be an option not yet explored [32]
	Type C: Inability to move eyes up and down. Learning and cognitive impairment		Type C: defect in cholesterol transport with secondary defect in A-SMase activity Excessive accumulation of cholesterol and sphingolipids [107]	Inhibition of glycosphingolipid synthesis prolonged lifespan in mouse model of type C [33]
Multiple Sclerosis-Experimental Autoimmune Encephalomyelitis (MS-EAE) [38,109]	Unpredictable and varies from person to person Loss of balance Loss of muscle coordination, resulting in tremors, bladder problems and slurred speech Problems with memory, attention, cognitive functions	Demyelination of axons	Lipid peroxidation products from ROS cPLA2 is highly expressed in EAE [25] sPLA2 levels increased prior to onset of symptoms T cells and auto-antibodies to Lipids [109] DHA levels ↓ [106]	Antioxidants [36] sPLA2 inhibition by CHEC-9 blocks inflammation [41] Ganglioside treatments prevent neuronal death
Huntington Disease [43,110]	Movement disorder Uncontrollable muscle movements Lack of concentration Memory loss Nuclear and cytoplasmic inclusion/Huntingtin	Striatal (caudate and putamen) neurons Degeneration of medium spiny striato-efferent GABAergic neurons, atrophy of caudate nucleus.	Trinucleotide CAG repeat expansion in the Huntingtin (Htt) gene is responsible for This polyglutamine disease.	Inhibiting 1) fatty acid amide hydrolase (FAAH), 2) monoacylglycerol lipase (MAGL) or 3) endocannabinoid membrane transporter (EMT) provided relief to HD patients [43,46] Ethyl- eicosapentaenoic acid (EPA) [48] Combination therapy (minocycline + Coenzyme Q10) [50]
Amyotrophic Lateral Sclerosis	Limb and muscle weakness, twitching and cramping of muscles	Progressive loss of cortical and spinal cord motorneurons	Lipid peroxidation [56]	Riluzole is the only available clinical agent [51] COX-2 inhibition was beneficial in mouse model [54]
	Lewy body like hyaline inclusion/SOD1 mutation
Schizophrenia	Disturbances in thinking, emotional reactions, and social behavior	Dorsalateral prefrontal cortex	Altered lipid metabolism may be responsible for defects in neurological development [57,58]	Antipsychotic drugs Eicosapentaenoic acid supplementation [57]
Bipolar disorder (manic depression illness)	Mood disorders characterized by episodes of mania and major depression	-	-	Combination of EPA and DHA [57]
Epilepsy	Wide range of severity Violent convulsions Loss of consciousness Minimal or no movements	Focal cortical area, later transferred to the Thalamus	DHA levels ↓ [106]	Ketogenic diet [64] Phenytoin [61] Second generation antiepileptic drugs [62]
Stroke [69]	Sudden weakness on one side of the body, loss of balance and coordination, trouble with cognition	Cerebral cortical Areas Striatum	Activation of Phospholipases (A2, C, D) [4,68], increased sPLA2 [111] cPLA2 knock out mice showed protection [4 and references Cited therein] DHA levels ↓ [106]	CDP-choline attenuated sPLA2 [68] Neuroprotectin D1 reduces infarct in MCAO model [91] sPLA2 inhibitors [112]
Traumatic Brain Injury [113]		Loss of CA3 hippocampal neurons	Aβ deposition, tau pathology [84]	Corticosteroids [81] apoE mimetic peptide showed benefit in experimental TBI [88]
Spinal Cord Injury [89]	Weakness and sensory loss; paralysis		Activation of PLA2, COX/LOX pathways. Corticosteroids inhibit These activations [81]	High-dose methylprednisolone in clinical use [89]; DHA treatment is beneficial [106]